Affinage

CLIP2

CAP-Gly domain-containing linker protein 2 · UniProt Q9UDT6

Length
1046 aa
Mass
115.8 kDa
Annotated
2026-04-28
100 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLIP2 (CLIP-115) is a brain-enriched cytoplasmic linker protein that tracks growing microtubule plus ends via two N-terminal microtubule-binding domains flanked by basic/serine-rich regions required for efficient microtubule association, and forms homodimers through its coiled-coil domain linked by disulfide bridges (PMID:9427243, PMID:10825300). Phosphorylation negatively regulates its microtubule-binding affinity, and it co-localizes with CLIP-170 at microtubule distal ends; CLIP2 interacts with CLASP proteins that stabilize microtubules at the cell leading edge in a PI3K/GSK-3β-dependent manner (PMID:10825300, PMID:11290329). In neurons, CLIP2 localizes to dendritic lamellar bodies and controls their distribution through microtubule association; knockout mice lacking CLIP2 exhibit neurological and behavioral deficits, though isolated CLIP2 haploinsufficiency in humans does not recapitulate the Williams-Beuren syndrome cognitive profile (PMID:9427243, PMID:14745832, PMID:22608712).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1997 High

    Establishing that CLIP2 is a brain-specific microtubule-binding protein linked to organelle positioning resolved its molecular identity and provided the first functional context — localizing to dendritic lamellar bodies whose distribution depends on intact microtubules.

    Evidence cDNA cloning, subcellular fractionation, immunolocalization, and microtubule depolymerization experiments in neurons

    PMID:9427243

    Open questions at the time
    • Structural basis for microtubule-binding domain selectivity was unresolved
    • Regulatory signals controlling CLIP-115 activity were unknown
    • In vivo loss-of-function phenotype had not been determined
  2. 2000 High

    Dissecting the domain requirements for microtubule binding showed that flanking basic/serine-rich regions are necessary beyond the conserved MTB domains, that phosphorylation inhibits binding, and that CLIP-115 homodimerizes via disulfide bridges — establishing key regulatory and structural principles.

    Evidence Deletion/point mutant transfection in COS-1 cells, microtubule co-sedimentation, in vitro phosphorylation, and disulfide cross-linking

    PMID:10825300

    Open questions at the time
    • Identity of the kinase(s) responsible for regulatory phosphorylation was unknown
    • Functional significance of CLIP-115/CLIP-170 co-localization at plus ends remained unresolved
    • Whether dimerization is required for in vivo function was untested
  3. 2001 High

    Identifying CLASPs as CLIP-115/CLIP-170 interactors that stabilize microtubules at the leading edge downstream of PI3K and GSK-3β placed CLIP2 within a signaling-regulated plus-end complex controlling cell polarity.

    Evidence Yeast two-hybrid, co-immunoprecipitation, overexpression in fibroblasts, and antibody microinjection

    PMID:11290329

    Open questions at the time
    • Whether the CLIP-115–CLASP interaction is direct or bridged was not fully resolved
    • Relative contributions of CLIP-115 versus CLIP-170 in recruiting CLASPs were unclear
    • Neuronal relevance of the PI3K/GSK-3β–CLASP–CLIP axis was not tested
  4. 2004 Medium

    Demonstrating that CLIP-115 knockout mice display neurological and behavioral deficits established that the protein's microtubule-regulatory function is essential for normal brain development and behavior.

    Evidence Knockout mouse phenotyping with neurological and behavioral analysis (reviewed)

    PMID:14745832

    Open questions at the time
    • Primary data were presented in a review context; detailed mechanistic dissection of neuronal deficits was lacking
    • Which neuronal cell types or circuits are most affected was unresolved
    • Relationship between microtubule dynamics defects and behavioral outcomes was correlative
  5. 2012 Medium

    Showing that isolated human CLIP2 haploinsufficiency does not produce the Williams-Beuren syndrome cognitive profile distinguished CLIP2's contribution from that of GTF2IRD1/GTF2I and refined the genotype–phenotype map of the WBS deletion region.

    Evidence Array CGH deletion mapping and cognitive testing in siblings with pure CLIP2 hemizygous deletion

    PMID:22608712

    Open questions at the time
    • Only a single family was studied, limiting generalizability
    • Subtle neurological phenotypes below the resolution of standard cognitive testing could be missed
    • Whether CLIP2 loss interacts epistatically with other WBS-region gene deletions was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The in vivo kinase(s) regulating CLIP2 phosphorylation, the structural basis for its selective plus-end tracking, and the specific neuronal circuits and developmental processes disrupted by CLIP2 loss remain unresolved.
  • No kinase or phosphatase acting on CLIP2 has been identified in vivo
  • No high-resolution structure of CLIP2 microtubule-binding domains exists
  • The neuronal cell-type-specific functions of CLIP2 are undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 1
Pathway
GO:0005856 cytoskeleton 3
Partners
CLASP1CLASP2CLIP1

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CLIP-115 (encoded by CLIP2) was identified as a novel brain-specific cytoplasmic linker protein that contains two N-terminal microtubule-binding domains and a long coiled-coil region. Direct experiments showed CLIP-115 binds microtubules and is enriched in dendritic lamellar bodies (DLBs); local microtubule depolymerization led to a temporary reduction of DLBs, establishing a role for CLIP-115 in brain-specific organelle translocation. cDNA cloning, subcellular fractionation, immunolocalization, microtubule depolymerization experiments in neurons Neuron High 9427243
2000 Efficient microtubule binding by CLIP-115 requires not only the conserved microtubule-binding (MTB) domains but also the flanking basic, serine-rich regions; phosphorylation negatively regulates microtubule binding. CLIP-115 accumulates at distal ends of growing microtubules in transfected COS-1 cells, co-localizing with CLIP-170. CLIP-115 forms homodimers linked by disulfide bridges in vitro, and Cys391 specifically controls microtubule bundling capacity of certain mutants. Transfection of deletion/point mutants in COS-1 cells, microtubule co-sedimentation assays, in vitro phosphorylation, live-cell imaging, in vitro disulfide cross-linking Journal of cell science High 10825300
2001 CLIP-115 and CLIP-170 associate with two CLIP-associated proteins (CLASPs), homologues of Drosophila Orbit/Mast. CLASPs bind CLIPs and microtubules, co-localize with CLIPs at microtubule distal ends, and have microtubule-stabilizing effects. After serum induction, CLASPs relocalize to distal microtubule segments at the leading edge in a PI3-kinase- and GSK-3β-dependent manner. Antibody injection showed CLASP2 is required for orientation of stabilized microtubules toward the leading edge. Yeast two-hybrid, co-immunoprecipitation, transfection/overexpression in fibroblasts, antibody microinjection, immunofluorescence microscopy Cell High 11290329
2004 CLIP-115 and CLIP-170 are discussed in the context of Williams Syndrome (WBS): knockout mice lacking CLIP-115 show distinct neurological and behavioral phenotypes, consistent with a role for CLIP-115 in the cytoskeletal regulation underlying the neurological symptoms of WBS. The review places CLIP-115 function downstream of microtubule network regulation in a developmental neurological context. Knockout mouse phenotyping (neurological and behavioral analysis) reviewed BioEssays Medium 14745832
2012 Genetic analysis of two healthy siblings with a pure hemizygous deletion of CLIP2 showed no physical or cognitive features of Williams-Beuren syndrome and average IQ without the WBS cognitive profile, demonstrating that CLIP2 haploinsufficiency alone is not sufficient to produce the WBS phenotype or cognitive profile, thus distinguishing CLIP2's contribution from that of GTF2IRD1 and GTF2I. Genomic deletion mapping (array CGH), cognitive testing (IQ assessment) in human patients with isolated CLIP2 hemizygous deletion American journal of human genetics Medium 22608712

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 2303 20371350
2009 Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 1440 19536157
2008 HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 1090 18978773
2016 Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nature methods 1054 27018577
2003 CLIP identifies Nova-regulated RNA networks in the brain. Science (New York, N.Y.) 888 14615540
2002 Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell 502 12110184
2005 CLIP: a method for identifying protein-RNA interaction sites in living cells. Methods (San Diego, Calif.) 475 16314267
2001 Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts. Cell 401 11290329
2011 Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data. Nature biotechnology 331 21633356
2010 HITS-CLIP: panoramic views of protein-RNA regulation in living cells. Wiley interdisciplinary reviews. RNA 312 21935890
2014 HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell reports 278 24613350
2018 Advances in CLIP Technologies for Studies of Protein-RNA Interactions. Molecular cell 231 29395060
2010 PAR-CliP--a method to identify transcriptome-wide the binding sites of RNA binding proteins. Journal of visualized experiments : JoVE 211 20644507
2002 LIS1, CLIP-170's key to the dynein/dynactin pathway. Molecular and cellular biology 208 11940666
2002 Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function. The Journal of cell biology 202 11889140
2015 CLIPdb: a CLIP-seq database for protein-RNA interactions. BMC genomics 184 25652745
2020 Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins. Genome biology 173 32252787
2016 Improving microRNA target prediction by modeling with unambiguously identified microRNA-target pairs from CLIP-ligation studies. Bioinformatics (Oxford, England) 172 26743510
2011 Identification of RNA-protein interaction networks using PAR-CLIP. Wiley interdisciplinary reviews. RNA 172 22213601
2005 EB1 and EB3 control CLIP dissociation from the ends of growing microtubules. Molecular biology of the cell 165 16148041
1992 Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats. Hypertension (Dallas, Tex. : 1979) 163 1333445
2010 AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nature cell biology 159 20495555
2004 Conformational changes in CLIP-170 regulate its binding to microtubules and dynactin localization. The Journal of cell biology 149 15381688
2017 CLIP Tool Kit (CTK): a flexible and robust pipeline to analyze CLIP sequencing data. Bioinformatics (Oxford, England) 142 27797762
2014 PAR-CLIP analysis uncovers AUF1 impact on target RNA fate and genome integrity. Nature communications 141 25366541
2011 RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Molecular and cellular neurosciences 141 21421050
2017 PureCLIP: capturing target-specific protein-RNA interaction footprints from single-nucleotide CLIP-seq data. Genome biology 115 29284540
2008 Molecular clip and tweezer introduce new mechanisms of enzyme inhibition. Journal of the American Chemical Society 108 18605724
2000 Functional analysis of CLIP-115 and its binding to microtubules. Journal of cell science 101 10825300
2015 Drosophila melanogaster clip-domain serine proteases: Structure, function and regulation. Biochimie 97 26453810
2014 Advancing the functional utility of PAR-CLIP by quantifying background binding to mRNAs and lncRNAs. Genome biology 93 24393468
1997 CLIP-115, a novel brain-specific cytoplasmic linker protein, mediates the localization of dendritic lamellar bodies. Neuron 92 9427243
2008 The microtubule-binding protein CLIP-170 coordinates mDia1 and actin reorganization during CR3-mediated phagocytosis. The Journal of cell biology 87 19114595
2002 The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO reports 86 12231510
2013 SNAP-, CLIP- and Halo-tag labelling of budding yeast cells. PloS one 82 24205303
2010 Phosphorylation of CLIP-170 by Plk1 and CK2 promotes timely formation of kinetochore-microtubule attachments. The EMBO journal 82 20664522
2018 Proximity-CLIP provides a snapshot of protein-occupied RNA elements in subcellular compartments. Nature methods 76 30478324
2014 PIPE-CLIP: a comprehensive online tool for CLIP-seq data analysis. Genome biology 75 24451213
2019 Chronic Low-grade Inflammatory Phenotype (CLIP) and Senescent Immune Dysregulation. Clinical therapeutics 74 30833113
2005 Interactions between CLIP-170, tubulin, and microtubules: implications for the mechanism of Clip-170 plus-end tracking behavior. Molecular biology of the cell 68 16120651
2004 LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome. BioEssays : news and reviews in molecular, cellular and developmental biology 67 14745832
2014 HITS-CLIP reveals key regulators of nuclear receptor signaling in breast cancer. Breast cancer research and treatment 61 24906430
1999 Purification and analysis of authentic CLIP-170 and recombinant fragments. The Journal of biological chemistry 61 10464331
2014 CapR: revealing structural specificities of RNA-binding protein target recognition using CLIP-seq data. Genome biology 55 24447569
2003 CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by different mechanisms. Cell motility and the cytoskeleton 54 12789661
2017 High-throughput identification of C/D box snoRNA targets with CLIP and RiboMeth-seq. Nucleic acids research 53 28031372
1999 Alf1p, a CLIP-170 domain-containing protein, is functionally and physically associated with alpha-tubulin. The Journal of cell biology 51 9885248
2018 Data Science Issues in Studying Protein-RNA Interactions with CLIP Technologies. Annual review of biomedical data science 50 37123514
2018 The Future of Cross-Linking and Immunoprecipitation (CLIP). Cold Spring Harbor perspectives in biology 48 30068528
2016 PAR-CLIP: A Method for Transcriptome-Wide Identification of RNA Binding Protein Interaction Sites. Methods in molecular biology (Clifton, N.J.) 46 26463383
2016 Optimization of PAR-CLIP for transcriptome-wide identification of binding sites of RNA-binding proteins. Methods (San Diego, Calif.) 46 27765618
2012 Microtubule-binding protein CLIP-170 is a mediator of paclitaxel sensitivity. The Journal of pathology 46 21989536
2013 Pregnenolone activates CLIP-170 to promote microtubule growth and cell migration. Nature chemical biology 45 23955365
2014 dCLIP: a computational approach for comparative CLIP-seq analyses. Genome biology 42 24398258
2013 A computational approach for identifying microRNA-target interactions using high-throughput CLIP and PAR-CLIP sequencing. BMC genomics 42 23368412
2012 CLIP (cross-linking and immunoprecipitation) identification of RNAs bound by a specific protein. Cold Spring Harbor protocols 36 23118367
2022 Positional motif analysis reveals the extent of specificity of protein-RNA interactions observed by CLIP. Genome biology 35 36085079
2017 CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome. Nucleic acids research 35 28934506
2012 The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome. American journal of human genetics 35 22608712
2021 A non-radioactive, improved PAR-CLIP and small RNA cDNA library preparation protocol. Nucleic acids research 34 33503264
2017 Computational analysis of CLIP-seq data. Methods (San Diego, Calif.) 34 28254606
2006 The CLIP-170 orthologue Bik1p and positioning the mitotic spindle in yeast. Current topics in developmental biology 33 17118263
2024 Decoding protein-RNA interactions using CLIP-based methodologies. Nature reviews. Genetics 29 38982239
2015 CLIPSeqTools--a novel bioinformatics CLIP-seq analysis suite. RNA (New York, N.Y.) 29 26577377
2014 CLIP-170 recruits PLK1 to kinetochores during early mitosis for chromosome alignment. Journal of cell science 29 24777477
2018 GoldCLIP: Gel-omitted Ligation-dependent CLIP. Genomics, proteomics & bioinformatics 28 29709556
2018 Recent computational developments on CLIP-seq data analysis and microRNA targeting implications. Briefings in bioinformatics 27 28605404
2014 Leveraging cross-link modification events in CLIP-seq for motif discovery. Nucleic acids research 27 25505146
2009 Probing interactions between CLIP-170, EB1, and microtubules. Journal of molecular biology 27 19913027
2008 Platinated copper(3-clip-phen) complexes as effective DNA-cleaving and cytotoxic agents. Chemistry (Weinheim an der Bergstrasse, Germany) 27 18293353
2015 Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas. Carcinogenesis 26 25957251
2013 Transcriptome-wide identification of RNA binding sites by CLIP-seq. Methods (San Diego, Calif.) 26 23545196
2009 Cdc2-mediated phosphorylation of CLIP-170 is essential for its inhibition of centrosome reduplication. The Journal of biological chemistry 25 19687009
2023 Towards in silico CLIP-seq: predicting protein-RNA interaction via sequence-to-signal learning. Genome biology 24 37542318
2018 omniCLIP: probabilistic identification of protein-RNA interactions from CLIP-seq data. Genome biology 24 30384847
2022 HCRNet: high-throughput circRNA-binding event identification from CLIP-seq data using deep temporal convolutional network. Briefings in bioinformatics 23 35189638
2014 HITS-CLIP (CLIP-Seq) for mouse Piwi proteins. Methods in molecular biology (Clifton, N.J.) 22 24178558
2014 HITS-CLIP and PAR-CLIP advance viral miRNA targetome analysis. Critical reviews in eukaryotic gene expression 21 24940765
2020 AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP-170. EMBO reports 20 33251722
2018 Cell type-specific CLIP reveals that NOVA regulates cytoskeleton interactions in motoneurons. Genome biology 20 30111345
2023 Serpin-1a and serpin-6 regulate the Toll pathway immune homeostasis by synergistically inhibiting the Spätzle-processing enzyme CLIP2 in silkworm, Bombyx mori. PLoS pathogens 19 37851691
2021 Functional characterization of two clip domain serine proteases in innate immune responses of Aedes aegypti. Parasites & vectors 19 34819136
2020 Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets. Genes 19 31947823
2018 Discovering circRNA-microRNA Interactions from CLIP-Seq Data. Methods in molecular biology (Clifton, N.J.) 19 29322451
2016 Genome-Wide Profiling of RNA-Protein Interactions Using CLIP-Seq. Methods in molecular biology (Clifton, N.J.) 19 26965263
2016 Identification of CELF1 RNA targets by CLIP-seq in human HeLa cells. Genomics data 19 27222809
2023 CLIP: accurate prediction of disordered linear interacting peptides from protein sequences using co-evolutionary information. Briefings in bioinformatics 18 36458437
2019 Identification, characterization, and expression analysis of clip-domain serine protease genes in the silkworm, Bombyx mori. Developmental and comparative immunology 18 31863792
2014 Computational Methods for CLIP-seq Data Processing. Bioinformatics and biology insights 18 25336930
2018 A clip domain serine protease regulates the expression of proPO and hemolymph clotting in mud crab, Scylla paramamosain. Fish & shellfish immunology 17 29747010
2018 Mapping multivalency in the CLIP-170-EB1 microtubule plus-end complex. The Journal of biological chemistry 17 30455356
2017 Has Sliding-Clip Renorrhaphy Eliminated the Need for Collecting System Repair During Robot-Assisted Partial Nephrectomy? Journal of endourology 17 27960537
2021 SOCS3-microtubule interaction via CLIP-170 and CLASP2 is critical for modulation of endothelial inflammation and lung injury. The Journal of biological chemistry 16 33372035
2020 Analysis of the nucleocytoplasmic shuttling RNA-binding protein HNRNPU using optimized HITS-CLIP method. PloS one 16 32302342
2013 Regulation of tumor angiogenesis by the microtubule-binding protein CLIP-170. Protein & cell 16 23549612
2020 Polypoid Atypical Spitz Tumor With a Fibrosclerotic Stroma, CLIP2-BRAF Fusion, and Homozygous Loss of 9p21. The American Journal of dermatopathology 15 31449064
2020 CLIP and Massively Parallel Functional Analysis of CELF6 Reveal a Role in Destabilizing Synaptic Gene mRNAs through Interaction with 3' UTR Elements. Cell reports 15 33357440
2018 PAR-CLIP for Discovering Target Sites of RNA-Binding Proteins. Methods in molecular biology (Clifton, N.J.) 15 29236251
2018 CLIP-related methodologies and their application to retrovirology. Retrovirology 15 29716635
2001 Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes. Proceedings of the National Academy of Sciences of the United States of America 15 11593032