Affinage

PAM

Peptidyl-glycine alpha-amidating monooxygenase · UniProt P19021

Length
973 aa
Mass
108.3 kDa
Annotated
2026-06-10
100 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAM is a multifunctional protein whose name reflects two distinct biochemical identities captured in this corpus. As peptidylglycine α-amidating monooxygenase, it is a type I integral membrane enzyme whose luminal domain houses two sequential catalytic cores—PHM, which performs copper- and ascorbate-dependent α-hydroxylation, and PAL, which cleaves the resulting peptidyl-α-hydroxyglycine to yield C-terminally amidated peptide and glyoxylate (PMID:26667899, PMID:8037462). This bifunctional amidation is the rate-limiting step in producing mature bioactive secretory peptides, demonstrated by loss-of-function studies in Drosophila where PHM nulls fail to amidate neuropeptides and die during development (PMID:10993678). The enzyme's intrinsically disordered cytosolic domain is dispensable for catalysis but essential for trafficking; it is phosphorylated by Uhmk1, and a cleaved soluble cytosolic fragment translocates to the nucleus to regulate expression of genes such as Aqp1, constituting a secretory-granule-to-nucleus signaling route (PMID:20573687, PMID:34089560). PAM is essential in mouse (knockout lethal at mid-gestation), and germline loss-of-function variants that impair its expression, trafficking, splicing, and amidation activity are associated with pituitary hypersecretion and adenoma (PMID:34089560, PMID:37388215). Separately, the same locus (also called MYCBP2/Pam) encodes a RING-finger E3 ubiquitin ligase that assembles a noncanonical SCF-like complex with FBXO45 and SKP1 but lacking CUL1; this complex polyubiquitinates substrates including TSC2/tuberin—thereby modulating mTOR signaling—and NMNAT2, controlling its proteasomal stability (PMID:18308511, PMID:29997255), and also targets the circadian receptor Rev-erbα for degradation to influence Clock gene expression (PMID:20534529). Additional regulatory activities include potent, S1P-induced long-lasting inhibition of adenylyl cyclase (PMID:15257286) and an RCC1 domain that binds and activates the neuronal KCC2 potassium-chloride cotransporter (PMID:18769030).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1985 Medium

    Establishing the genomic architecture of the amidated-peptide system showed that hormone-coding exons carry their own post-translational processing signals, framing amidation as a programmed maturation step.

    Evidence DNA sequencing and gene structure analysis of the human VIP/PHM-27 precursor gene

    PMID:2839091 PMID:2987932

    Open questions at the time
    • Does not characterize the amidating enzyme itself
    • Promoter regulation studied only in neuroblastoma cells
  2. 1994 High

    Purification of the membrane enzyme to homogeneity defined PAM as a bifunctional type I integral membrane protein whose two catalytic activities can be physically separated, answering how a single protein performs two sequential reactions.

    Evidence Affinity purification from transfected HEK-293 membranes, in vitro enzymatic assays, limited proteolysis releasing monofunctional PHM

    PMID:8037462

    Open questions at the time
    • Atomic-resolution catalytic mechanism not yet resolved
    • Physiological role of membrane vs soluble forms unclear
  3. 2000 High

    Genetic ablation in Drosophila established PHM/PAM as the rate-limiting and essential enzyme for peptide amidation in vivo, showing amidation is required for organismal viability.

    Evidence Null and hypomorph alleles, transgenic rescue, enzyme activity assay, neuropeptide immunodetection

    PMID:10993678

    Open questions at the time
    • Specific amidated peptides essential for survival not pinpointed
    • Mammalian requirement not addressed here
  4. 2003 Medium

    Identification of PAM/MYCBP2 binding to the TSC1-TSC2 complex via its RING domain connected the locus to mTOR-pathway regulation and growth-cone biology.

    Evidence Co-IP, yeast two-hybrid, neuronal co-localization, Drosophila genetic epistasis with Tsc1/Tsc2

    PMID:14559897

    Open questions at the time
    • Ubiquitination of tuberin not demonstrated in this study
    • Direct enzymatic activity inferred not shown
  5. 2004 High

    Discovery that PAM is an S1P-recruited, long-lasting inhibitor of adenylyl cyclase added a membrane-signaling function distinct from amidation.

    Evidence Subcellular localization, S1P identification as serum factor, adenylyl cyclase activity assay, PAM knockdown

    PMID:15257286

    Open questions at the time
    • Molecular mechanism of cyclase inhibition unresolved
    • Which PAM form/domain mediates this is unclear
  6. 2008 High

    Demonstration that PAM functions as a bona fide RING E3 ligase that ubiquitinates tuberin and self-ubiquitinates, with TSC1 protection, defined its mechanism of mTOR regulation.

    Evidence In vitro ubiquitination with RING mutagenesis, Co-IP, neuronal RNAi with mTOR readout

    PMID:18308511

    Open questions at the time
    • E2 partner identity not fully defined
    • Ubiquitin chain topology not characterized
  7. 2008 High

    Mapping the RCC1 domain interaction with KCC2 revealed a non-catalytic role in activating neuronal chloride transport.

    Evidence Yeast two-hybrid, GST pull-down, Co-IP, 86Rb ion flux assay, point mutagenesis of binding region

    PMID:18769030

    Open questions at the time
    • Mechanism by which RCC1 binding activates transport unknown
    • In vivo relevance to neuronal chloride homeostasis untested here
  8. 2010 High

    Linking PAM/MYCBP2 to Rev-erbα ubiquitination extended its E3 ligase role into circadian regulation.

    Evidence Co-purification, RNAi stabilization of Rev-erbα, ubiquitination and protein stability assays in mouse hepatoma cells

    PMID:20534529

    Open questions at the time
    • Direct vs indirect ubiquitination of Rev-erbα not fully separated from Arf-bp1 contribution
    • Complex composition for this substrate undefined
  9. 2010 High

    Identification of Uhmk1 phosphorylation of the cytosolic domain and nuclear translocation of a cleaved CD fragment established a secretory-granule-to-nucleus retrograde signaling pathway controlling gene expression.

    Evidence Kinase assay, subcellular fractionation, phosphomimetic mutagenesis, microarray, Pam+/- mouse validation

    PMID:20573687

    Open questions at the time
    • Protease that generates the CD fragment not identified
    • Direct DNA/transcription-factor targets of CD unknown
  10. 2018 High

    Reconstitution of a noncanonical CUL1-lacking SCF-like complex (PAM/FBXO45/SKP1) targeting NMNAT2 defined the molecular architecture of PAM's ligase module and its role in NMNAT2 turnover.

    Evidence Co-IP, biochemical complex reconstitution, in vitro ubiquitination, proteasome degradation assay

    PMID:29997255

    Open questions at the time
    • How substrate selection switches between TSC2, NMNAT2, and Rev-erbα is unresolved
    • Structural model of the assembled complex absent
  11. 2021 Medium

    Mouse knockout lethality plus conservation in a ciliated unicellular eukaryote established PAM as an ancient, essential enzyme and assigned the cytosolic domain a trafficking-specific, catalysis-independent role.

    Evidence Mouse knockout, phylogenetic analysis, Chlamydomonas localization, domain characterization (review synthesis)

    PMID:34089560

    Open questions at the time
    • Species differences in trafficking mechanism unexplained
    • Cause of mid-gestation lethality not defined molecularly
  12. 2023 Medium

    Functional testing of germline loss-of-function variants tied reduced PAM amidation function to human pituitary hypersecretion and adenoma, providing a disease link.

    Evidence Germline sequencing with in vitro expression, trafficking, minigene splicing, and amidation activity assays

    PMID:37388215

    Open questions at the time
    • Single-lab functional validation
    • Mechanism connecting reduced amidation to hypersecretion not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dual identities—amidating enzyme versus RING E3 ligase—relate at the level of gene products, and how the ligase selects among its diverse substrates, remains unresolved.
  • No structural model of the substrate-recognition switch
  • Relationship between the amidation and ubiquitination functions of the locus unclear in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0016740 transferase activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005929 cilium 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-9909396 Circadian clock 1
Partners
FBXO45KCC2NMNAT2REV-ERBΑSKP1TSC1TSC2UHMK1
Complex memberships
noncanonical SCF-like complex (PAM/FBXO45/SKP1, lacking CUL1)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 PAM (peptidylglycine α-amidating monooxygenase) catalyzes C-terminal amidation of peptidylglycine substrates in two sequential steps: the PHM (peptidylglycine α-hydroxylating monooxygenase) domain catalyzes copper- and ascorbate-dependent α-hydroxylation, and the PAL (peptidyl-α-hydroxyglycine α-amidating lyase) domain cleaves the N-C bond to produce amidated peptide and glyoxylate. Both catalytic cores are contained within the luminal domain of PAM, a type 1 integral membrane protein, and crystal structures of both catalytic cores have been determined revealing interactions with metals, molecular oxygen, and substrate. Biochemical purification, enzymatic assay, structural determination (crystallography), cloning Journal of molecular endocrinology High 26667899
2000 In Drosophila, PHM (the ortholog of human PAM's PHM domain) is the rate-limiting enzyme for C-terminal α-amidation of secretory peptides. PHM null mutants lack PHM protein and enzyme activity, die as late embryos or young larvae, and show near-complete absence of amidated peptides while peptide precursors, non-amidated neuropeptides, and other biosynthetic enzymes remain detectable. PHM is required throughout the life of Drosophila for peptide amidating activity. Genetic loss-of-function (null mutants, hypomorphs), transgenic rescue, enzymatic activity assay, immunodetection of neuropeptides Developmental biology High 10993678
1994 PAM-1, a type I integral membrane protein, was purified to homogeneity from stably transfected HEK-293 cell membranes. Purified PAM-1 exhibits an acidic pH optimum and lower maximal velocity than soluble bifunctional PAM. Limited tryptic digestion of PAM-1 releases monofunctional PHM (peptidylglycine α-hydroxylating monooxygenase), increasing its specific activity ~fourfold and shifting its pH optimum to match that of PAL (peptidyl-α-hydroxyglycine α-amidating lyase). Affinity chromatography purification, enzymatic activity assay (in vitro), limited proteolysis Archives of biochemistry and biophysics High 8037462
2010 PAM (also called Myc-bp2/MYCBP2) and Arf-bp1 are E3 ubiquitin ligases that co-purify with the circadian heme receptor Rev-erb alpha and are required for its ubiquitination. RNA interference-mediated depletion of Arf-bp1 and Pam stabilizes Rev-erb alpha protein and protects it from degradation triggered by lithium or serum shock, thereby modulating Clock gene expression and circadian function in mouse hepatoma cells. Co-purification (biochemical), RNA interference (RNAi) knockdown, ubiquitination assay, protein stability assay Proceedings of the National Academy of Sciences of the United States of America High 20534529
2003 Pam (Protein associated with Myc/MYCBP2) physically associates with the tuberin-hamartin (TSC2-TSC1) complex in the brain. The C-terminal RING zinc finger domain of Pam binds to tuberin. Pam co-localizes with tuberin and hamartin in neurites and growth cones of cortical neurons. Genetic studies in Drosophila showed that Highwire (the Pam ortholog) can genetically interact with the Tsc1·Tsc2 complex and negatively regulate its activity. Co-immunoprecipitation, yeast two-hybrid, co-localization (immunofluorescence), Drosophila genetic epistasis The Journal of biological chemistry Medium 14559897
2008 Pam (MYCBP2) functions as an E3 ubiquitin ligase: it associates with E2 ubiquitin-conjugating enzymes and ubiquitinates tuberin (TSC2) through its RING finger domain in mammalian cells. Tuberin ubiquitination by Pam is independent of its phosphorylation by Akt, RSK1, or ERK. Pam also self-ubiquitinates via its RING finger domain. The TSC1 protein hamartin protects tuberin from Pam-mediated ubiquitination, but fails to protect a disease-associated TSC2 missense mutant. Pam knockdown by RNAi in rat primary neurons elevates tuberin levels and inhibits mTOR signaling. In vitro ubiquitination assay, co-immunoprecipitation, RNAi knockdown, mTOR pathway readout, domain mutagenesis (RING finger) Cellular signalling High 18308511
2018 Human PAM (MYCBP2) forms a noncanonical SCF-like ubiquitin ligase complex containing FBXO45 and SKP1 but lacking CUL1. FBXO45 is important for assembly of the PAM/FBXO45/SKP1 complex rather than solely for substrate recognition. SKP1 acts as an auxiliary component of the target recognition module, enhancing FBXO45 binding to NMNAT2. PAM polyubiquitinates NMNAT2 and regulates NMNAT2 protein stability and degradation by the proteasome. Co-immunoprecipitation, biochemical reconstitution of complex, in vitro ubiquitination assay, proteasome degradation assay The Journal of biological chemistry High 29997255
2004 PAM (Protein Associated with Myc/MYCBP2) is one of the most potent inhibitors of adenylyl cyclase activity. PAM localizes at the endoplasmic reticulum in HeLa cells and is recruited to the plasma membrane upon treatment with sphingosine-1-phosphate (S1P), causing inhibition of adenylyl cyclase activity. S1P-induced late-phase adenylyl cyclase inhibition (20–240 min) is PAM-dependent, whereas the initial phase (1–10 min) is Gi-mediated and PAM-independent. This makes PAM the longest-lasting nontranscriptional regulator of adenylyl cyclase activity known. Subcellular fractionation/localization, purification of S1P as serum factor, adenylyl cyclase activity assay, PAM knockdown The EMBO journal High 15257286
2010 The cytosolic domain (CD) of PAM (peptidylglycine α-amidating monooxygenase) is basally phosphorylated by Uhmk1 (U2AF homology motif kinase 1) and other Ser/Thr kinases. Endoproteolytic cleavage of PAM releases a soluble CD fragment that localizes to the nucleus. Nuclear localization of PAM-CD is decreased by phosphomimetic mutations in PAM-CD or by overexpression of active Uhmk1. PAM-CD can increase expression of a subset of genes including aquaporin 1 (Aqp1) in AtT-20 cells, and this relationship was confirmed in vivo in Pam heterozygous mice. Kinase assay (phosphorylation), subcellular fractionation/localization, microarray gene expression, transgenic mouse (Pam+/- vs Pam+/+), phosphomimetic mutagenesis Molecular endocrinology High 20573687
2007 The basic helix-loop-helix protein DIMMED (DIMM) directly activates transcription of the PHM gene (Drosophila ortholog of human PAM) in peptidergic neurons. DIMM activity requires its basic region and three E-box sites within PHM's first intron. All three E-boxes contribute to transcriptional activation and interact cooperatively. The mammalian DIMM ortholog MIST1 also transactivates the PHM gene. In vivo PHM regulatory region expression requires dimm function. Transfection/reporter assay in HEK293 cells, site-directed mutagenesis of E-box sites, in vivo Drosophila genetics (dimm mutants), ChIP-equivalent reporter analysis Molecular and cellular biology High 17967878
2008 The RCC1 (Regulator of Chromatin Condensation) domain of PAM (Protein Associated with Myc) binds to the carboxyl terminus of the neuronal KCC2 potassium-chloride cotransporter. This interaction was identified by yeast two-hybrid, confirmed by GST pull-down, and co-immunoprecipitation after co-expression in HEK293 cells. Functional 86Rb/K+ uptake assays showed that RCC1/PAM causes increased KCC2-mediated ion flux. A point mutation in the 20-amino-acid KCC2 binding region abolishes both the RCC1/PAM interaction and N-ethylmaleimide activation of KCC2. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, ion flux assay (86Rb uptake), site-directed mutagenesis Cellular physiology and biochemistry High 18769030
2021 PAM (peptidylglycine α-amidating monooxygenase) is essential; mice lacking PAM survive only until mid-gestation. PAM is present in cilia of Chlamydomonas reinhardtii (a unicellular eukaryote lacking secretory granules), suggesting PAM-like enzyme was present in the last eukaryotic common ancestor. Despite similar catalytic features between human and C. reinhardtii PAM, trafficking of PAM differs between species. The intrinsically disordered cytosolic domain of PAM is not essential for catalytic activity but is essential for PAM trafficking. Genetic knockout (mouse), phylogenetic analysis, biochemical characterization, cell biological localization studies The FEBS journal Medium 34089560
2023 Germline loss-of-function variants in the PAM gene (encoding peptidylglycine α-amidating monooxygenase) are enriched in subjects with pituitary hypersecretion. Functional testing of identified PAM variants in vitro demonstrated deleterious effects on protein expression, protein trafficking (Western blotting), mRNA splicing (minigene assays), and amidation activity (cell lysate and serum amidation assays), confirming that reduced PAM function is associated with pituitary adenoma and hypersecretion. Germline sequencing, Western blotting, minigene splicing assay, enzymatic amidation activity assay in cell lysates and serum Frontiers in endocrinology Medium 37388215
2002 PAM (Protein Associated with Myc/MYCBP2) mRNA is highly expressed in specific brain regions including hippocampus, dentate gyrus, and cerebellum, restricted to pyramidal cells of hippocampus and granule cells of dentate gyrus and cerebellum. PAM mRNA expression is developmentally regulated: it is turned on after birth and upregulated during the first postnatal two weeks, then remains elevated into adulthood. No alterations in PAM mRNA expression are detected in mice deficient in adenylyl cyclase isoforms I or VIII. In situ hybridization, developmental time course analysis, adenylyl cyclase knockout mouse analysis Brain research. Developmental brain research Low 12036515
1985 The human precursor gene for VIP and PHM-27 was characterized: PHM-27 (the human ortholog of PHI, with N-terminal histidine and C-terminal methionine amide) and VIP are encoded on two separate, adjacent exons separated by a 0.75-kb intron. Each exon encodes both the hormone amino acid residues and post-translational processing signal sequences. The 3' splice sites of the two exons contain an identical stretch of nine nucleotides, suggesting possible alternative RNA processing. Oligodeoxynucleotide probe hybridization, direct DNA sequencing, gene structure analysis Proceedings of the National Academy of Sciences of the United States of America Medium 2987932
1988 The complete human VIP/PHM-27 gene spans 8,837 bp and consists of seven exons and six introns. PHM-27 is encoded by exon IV and VIP by exon V. The VIP- and PHM-27-encoding exons are homologous, suggesting duplication from an ancestral exon. The functional promoter (28 bp upstream of the cap site) is inducible by cAMP and phorbol esters in human neuroblastoma cells. DNA sequencing, primer extension, exon mapping, mung bean nuclease mapping, promoter-reporter assay Annals of the New York Academy of Sciences Medium 2839091
2010 In Schistosoma mansoni, a monofunctional PAL (SmPAL) enzyme was identified that has functionally similar catalytic activity to the PAL domain of human bifunctional PAM but shows key catalytic core amino acid substitutions. SmPAL mRNA is expressed in neuronal cell bodies of the central nervous system of adult schistosomes, consistent with its role in amidating neuropeptides for neuromuscular function. Heterologous expression and enzymatic characterization, in situ hybridization, RNAi (knockdown attempted with variable success) Molecular and biochemical parasitology Low 20488212

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 1274 26098369
2018 Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. Nature 1168 29512652
2014 Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease. Nature 989 25079318
2017 Engineered Cpf1 variants with altered PAM specificities. Nature biotechnology 327 28581492
2016 Identifying and Visualizing Functional PAM Diversity across CRISPR-Cas Systems. Molecular cell 251 27041224
2020 PAM recognition by miniature CRISPR-Cas12f nucleases triggers programmable double-stranded DNA target cleavage. Nucleic acids research 239 32246713
2017 Structural Basis for the Canonical and Non-canonical PAM Recognition by CRISPR-Cpf1. Molecular cell 213 28781234
2021 CRISPR technologies and the search for the PAM-free nuclease. Nature communications 209 33483498
2016 PAM-Dependent Target DNA Recognition and Cleavage by C2c1 CRISPR-Cas Endonuclease. Cell 208 27984729
2018 Minimal PAM specificity of a highly similar SpCas9 ortholog. Science advances 180 30397647
2018 PAM identification by CRISPR-Cas effector complexes: diversified mechanisms and structures. RNA biology 179 30109815
2021 PAM-less plant genome editing using a CRISPR-SpRY toolbox. Nature plants 170 33398158
2016 Deciphering, Communicating, and Engineering the CRISPR PAM. Journal of molecular biology 126 27916599
2016 Structural Basis for the Altered PAM Specificities of Engineered CRISPR-Cas9. Molecular cell 118 26990991
1990 Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). The Journal of clinical investigation 110 2318966
2020 An engineered ScCas9 with broad PAM range and high specificity and activity. Nature biotechnology 104 32393822
2020 A Cas9 with PAM recognition for adenine dinucleotides. Nature communications 92 32424114
2019 Genome Engineering in Rice Using Cas9 Variants that Recognize NG PAM Sequences. Molecular plant 88 30928636
2010 E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proceedings of the National Academy of Sciences of the United States of America 87 20534529
1985 Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome. Proceedings of the National Academy of Sciences of the United States of America 82 2987932
2018 Cas4 Nucleases Define the PAM, Length, and Orientation of DNA Fragments Integrated at CRISPR Loci. Molecular cell 81 29883605
2021 Engineered prime editors with PAM flexibility. Molecular therapy : the journal of the American Society of Gene Therapy 80 33636398
2017 Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1. Molecular cell 78 28595896
2000 PHM is required for normal developmental transitions and for biosynthesis of secretory peptides in Drosophila. Developmental biology 74 10993678
2015 60 YEARS OF POMC: From POMC and α-MSH to PAM, molecular oxygen, copper, and vitamin C. Journal of molecular endocrinology 71 26667899
2003 Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. The Journal of biological chemistry 70 14559897
2008 Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. Cellular signalling 65 18308511
2022 PAM-less conditional DNA substrates leverage trans-cleavage of CRISPR-Cas12a for versatile live-cell biosensing. Chemical science 61 35308851
1986 The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. Peptides 60 3018707
2022 PhieABEs: a PAM-less/free high-efficiency adenine base editor toolbox with wide target scope in plants. Plant biotechnology journal 57 34984801
2018 PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling? Trends in pharmacological sciences 55 29885909
2020 High-Throughput Screens of PAM-Flexible Cas9 Variants for Gene Knockout and Transcriptional Modulation. Cell reports 54 32130891
2023 PAM-flexible genome editing with an engineered chimeric Cas9. Nature communications 51 37794046
2007 The Drosophila basic helix-loop-helix protein DIMMED directly activates PHM, a gene encoding a neuropeptide-amidating enzyme. Molecular and cellular biology 48 17967878
2004 PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. The EMBO journal 47 15257286
2013 Genetic determinants of PAM-dependent DNA targeting and pre-crRNA processing in Sulfolobus islandicus. RNA biology 46 23392249
1986 Effects of VIP, PHM and substance P on blood vessels and secretory elements of the human submandibular gland. Regulatory peptides 46 2422707
2025 Custom CRISPR-Cas9 PAM variants via scalable engineering and machine learning. Nature 44 40262634
2022 PAM-independent ultra-specific activation of CRISPR-Cas12a via sticky-end dsDNA. Nucleic acids research 43 36484104
2020 Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells. International journal of molecular sciences 41 32070055
2018 PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2. The Journal of biological chemistry 41 29997255
2020 Characterization of Cas12a nucleases reveals diverse PAM profiles between closely-related orthologs. Nucleic acids research 40 32329776
2024 PAM-Engineered Toehold Switches as Input-Responsive Activators of CRISPR-Cas12a for Sensing Applications. Angewandte Chemie (International ed. in English) 39 38284432
2022 Genome editing in animals with minimal PAM CRISPR-Cas9 enzymes. Nature communications 38 35552388
2021 Scalable characterization of the PAM requirements of CRISPR-Cas enzymes using HT-PAMDA. Nature protocols 38 33547443
2019 Cas4-Cas1 fusions drive efficient PAM selection and control CRISPR adaptation. Nucleic acids research 38 30937444
2010 Signaling from the secretory granule to the nucleus: Uhmk1 and PAM. Molecular endocrinology (Baltimore, Md.) 38 20573687
2024 A PAM-Free One-Step Asymmetric RPA and CRISPR/Cas12b Combined Assay (OAR-CRISPR) for Rapid and Ultrasensitive DNA Detection. Analytical chemistry 37 38551977
2000 Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM). Human pathology 37 10987251
2019 Structural basis for the promiscuous PAM recognition by Corynebacterium diphtheriae Cas9. Nature communications 34 31036811
2019 The post-PAM interaction of RNA-guided spCas9 with DNA dictates its target binding and dissociation. Science advances 34 31763447
2021 PAM-repeat associations and spacer selection preferences in single and co-occurring CRISPR-Cas systems. Genome biology 33 34593010
2021 Efficient and high-fidelity base editor with expanded PAM compatibility for cytidine dinucleotide. Science China. Life sciences 32 33420918
1994 Purification and characterization of PAM-1, an integral membrane protein involved in peptide processing. Archives of biochemistry and biophysics 32 8037462
1984 Production of VIP- and PHM (human PHI)-related peptides in human neuroblastoma cells. Peptides 32 6548020
2023 Molecular basis and engineering of miniature Cas12f with C-rich PAM specificity. Nature chemical biology 31 37697004
2022 DNA topology regulates PAM-Cas9 interaction and DNA unwinding to enable near-PAMless cleavage by thermophilic Cas9. Molecular cell 30 36272409
2024 PAM-flexible Engineered FnCas9 variants for robust and ultra-precise genome editing and diagnostics. Nature communications 29 38942756
2022 PCDetection: PolyA-CRISPR/Cas12a-based miRNA detection without PAM restriction. Biosensors & bioelectronics 29 35797934
1988 Complete nucleotide sequence of human vasoactive intestinal peptide/PHM-27 gene and its inducible promoter. Annals of the New York Academy of Sciences 29 2839091
2021 Cas12a variants designed for lower genome-wide off-target effect through stringent PAM recognition. Molecular therapy : the journal of the American Society of Gene Therapy 28 34687846
2019 Efficient cleavage resolves PAM preferences of CRISPR-Cas in human cells. Cell regeneration (London, England) 28 31709036
2021 Engineering a PAM-flexible SpdCas9 variant as a universal gene repressor. Nature communications 27 34824292
1985 Evidence for common precursors but differential processing of VIP and PHM in VIP-producing tumors. Peptides 26 3840886
2020 Programming PAM antennae for efficient CRISPR-Cas9 DNA editing. Science advances 24 32494703
2017 Methods for decoding Cas9 protospacer adjacent motif (PAM) sequences: A brief overview. Methods (San Diego, Calif.) 24 28344037
2007 Unconventional binding sites and receptors for VIP and related peptides PACAP and PHI/PHM: an update. Peptides 24 17555844
2021 Compact SchCas9 Recognizes the Simple NNGR PAM. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 34874112
2021 Engineered dual selection for directed evolution of SpCas9 PAM specificity. Nature communications 22 33441553
2022 Rapid detection of multiple SARS-CoV-2 variants of concern by PAM-targeting mutations. Cell reports methods 21 35156077
2019 Construction of non-canonical PAM-targeting adenosine base editors by restriction enzyme-free DNA cloning using CRISPR-Cas9. Scientific reports 21 30894632
2019 Molecular basis for the PAM expansion and fidelity enhancement of an evolved Cas9 nuclease. PLoS biology 21 31603896
2017 Genome-wide analysis of long noncoding RNA profiling in PRRSV-infected PAM cells by RNA sequencing. Scientific reports 21 28694521
2002 Developmental expression of PAM (protein associated with MYC) in the rodent brain. Brain research. Developmental brain research 21 12036515
2023 Anti-CRISPR AcrIIC5 is a dsDNA mimic that inhibits type II-C Cas9 effectors by blocking PAM recognition. Nucleic acids research 18 36744495
2023 Completely Free from PAM Limitations: Asymmetric RPA with CRISPR/Cas12a for Nucleic Acid Assays. ACS sensors 18 38010352
2022 Molecular Mechanism of D1135E-Induced Discriminated CRISPR-Cas9 PAM Recognition. Journal of chemical information and modeling 18 35666156
2022 seRNA PAM controls skeletal muscle satellite cell proliferation and aging through trans regulation of Timp2 expression synergistically with Ddx5. Aging cell 18 35851988
2022 PAM binding ensures orientational integration during Cas4-Cas1-Cas2-mediated CRISPR adaptation. Molecular cell 18 36272411
2024 Bacteriophage λ exonuclease and a 5'-phosphorylated DNA guide allow PAM-independent targeting of double-stranded nucleic acids. Nature biotechnology 17 39294394
2023 A universal and specific RNA biosensor via DNA circuit-mediated PAM-independent CRISPR/Cas12a and PolyA-rolling circle amplification. Biosensors & bioelectronics 17 36774734
2023 PAM-flexible Cas9-mediated base editing of a hemophilia B mutation in induced pluripotent stem cells. Communications medicine 17 37076593
2023 Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion. Frontiers in endocrinology 17 37388215
2020 Pam3CSK4-CDGSF Augments Antitumor Immunotherapy by Synergistically Activating TLR1/2 and STING. Bioconjugate chemistry 17 33147965
1994 Location of PHM/VIP mRNA in human gastrointestinal tract detected by in situ hybridization. Cell and tissue research 17 8020060
2008 The RCC1 domain of protein associated with Myc (PAM) interacts with and regulates KCC2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 18769030
2025 PAM-Independent CRISPR-Cas12a System for Specific Assays of Single Nucleotide Variants. JACS Au 15 40151256
2024 TracrRNA reprogramming enables direct PAM-independent detection of RNA with diverse DNA-targeting Cas12 nucleases. Nature communications 15 39003282
2022 Expanding the Scope of Bacterial CRISPR Activation with PAM-Flexible dCas9 Variants. ACS synthetic biology 15 36378874
2023 A Cas12a ortholog with distinct TTNA PAM enables sensitive detection of HPV16/18. Cell reports methods 14 37159673
2022 CRISPRactivation-SMS, a message for PAM sequence independent gene up-regulation in Escherichia coli. Nucleic acids research 14 36134715
2021 PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging. Aging 14 33472174
2021 Efficient DNA interrogation of SpCas9 governed by its electrostatic interaction with DNA beyond the PAM and protospacer. Nucleic acids research 13 34850124
2020 PAM haploinsufficiency does not accelerate the development of diet- and human IAPP-induced diabetes in mice. Diabetologia 13 31984442
2022 Cell Type-Specific Anti-Adhesion Properties of Peritoneal Cell Treatment with Plasma-Activated Media (PAM). Biomedicines 12 35453677
2022 Abscisic acid-polyacrylamide (ABA-PAM) treatment enhances forage grass growth and soil microbial diversity under drought stress. Frontiers in plant science 12 36119590
2021 PAM: diverse roles in neuroendocrine cells, cardiomyocytes, and green algae. The FEBS journal 12 34089560
2021 CABE-RY: A PAM-flexible dual-mutation base editor for reliable modeling of multi-nucleotide variants. Molecular therapy. Nucleic acids 12 34513298
2010 A PAL for Schistosoma mansoni PHM. Molecular and biochemical parasitology 12 20488212
2017 Effect of SLC34A2 gene mutation on extracellular phosphorus transport in PAM alveolar epithelial cells. Experimental and therapeutic medicine 11 29375690

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