Affinage

HPS3

BLOC-2 complex member HPS3 · UniProt Q969F9

Length
1004 aa
Mass
113.7 kDa
Annotated
2026-06-10
62 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HPS3 is a subunit of BLOC-2, a stable ~340 kDa peripheral membrane complex it forms with HPS5 and HPS6 that directs cargo trafficking to lysosome-related organelles (PMID:15030569, PMID:14718540). HPS3 functions in a complex distinct from the HPS1/HPS4-containing BLOC-3, with which it does not associate (PMID:12847290). Within BLOC-2, the subunits are mutually stabilizing: loss of HPS3 destabilizes HPS5 and HPS6 in both mouse tissues and human patient cells, establishing that complex integrity depends on all subunits (PMID:14718540, PMID:30387913). HPS3 carries a functional clathrin-binding motif (LLDFE, residues 172–176) through which it associates with clathrin on perinuclear vesicles, and deletion of this motif abolishes clathrin co-localization and renders the protein cytoplasmic (PMID:16159387). Functionally, HPS3 selectively controls trafficking of a defined subset of melanocyte cargo — tyrosinase, Tyrp1, Dct, and LAMP1/LAMP3 — to melanosomes, with other melanosomal and endosomal markers unaffected (PMID:15632015, PMID:15675963), and is independently required for platelet dense-granule biogenesis and secretion, such that its loss in mice abolishes dense-granule-dependent thrombus formation (PMID:19687360). At endolysosomes, the HPS3 subunit recruits BLOC-2 to the compartment where it promotes WASH complex recruitment and lysosome maturation (PMID:39059394). Loss-of-function mutation of HPS3 causes Hermansky-Pudlak syndrome type 3 (PMID:11455388).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Established HPS3 as a disease gene by linking a founder deletion to a distinct form of Hermansky-Pudlak syndrome, implicating it in vesicle formation in specialized cells.

    Evidence Homozygosity mapping and positional cloning with mutation analysis in a Puerto Rican genetic isolate

    PMID:11455388

    Open questions at the time
    • No molecular function or interacting partners defined
    • Cell-type-specific trafficking role not yet demonstrated
  2. 2003 Medium

    Resolved which complex HPS3 belongs to by showing it does not associate with HPS1, distinguishing its pathway from the BLOC-3 (HPS1/HPS4) complex.

    Evidence Sedimentation-velocity fractionation and co-immunoprecipitation from HeLa cell extracts

    PMID:12847290

    Open questions at the time
    • Did not identify HPS3's own complex partners
    • Membrane association unexplained
  3. 2004 High

    Defined the BLOC-2 complex by demonstrating that HPS3, HPS5, and HPS6 assemble into a single ~340 kDa peripheral membrane complex with mutually dependent subunit stability.

    Evidence Co-IP, size-exclusion chromatography, and density gradient centrifugation in HeLa cells, plus mouse tissue co-sedimentation and double-mutant epistasis

    PMID:14718540 PMID:15030569

    Open questions at the time
    • Stoichiometry and architecture not resolved
    • Molecular activity of the complex undefined
    • Membrane recruitment mechanism unknown
  4. 2005 High

    Provided a mechanistic link to membrane trafficking machinery by identifying a functional clathrin-binding motif in HPS3 mediating localization to perinuclear clathrin-coated vesicles.

    Evidence Co-IP from melanocytes, temperature-block live-cell imaging, immunoEM, and clathrin-binding-domain deletion mutagenesis

    PMID:16159387

    Open questions at the time
    • Functional consequence of clathrin binding for cargo sorting not directly tested
    • Whether other BLOC-2 subunits also engage clathrin unknown
  5. 2005 Medium

    Defined the cargo specificity of HPS3 by showing it selectively controls melanosomal delivery of a defined subset of proteins while sparing other markers.

    Evidence Immunocytochemistry, confocal and ultrastructural analysis of HPS-3 patient-derived melanocytes across multiple cargo markers, including comparison with HPS-1 and HPS-2

    PMID:15632015 PMID:15675963

    Open questions at the time
    • Mechanism distinguishing affected from unaffected cargo not established
    • Direct cargo recognition by BLOC-2 not demonstrated
  6. 2009 High

    Demonstrated a second physiological role beyond pigmentation by showing HPS3 is specifically required for platelet dense-granule biogenesis and secretion-dependent thrombosis.

    Evidence HPS3-knockout mouse platelet function assays, flow cytometry, and in vivo FeCl3 arterial thrombosis model

    PMID:19687360

    Open questions at the time
    • Molecular step within dense-granule biogenesis controlled by HPS3 not pinpointed
    • Whether the clathrin/BLOC-2 mechanism operates identically in platelets unaddressed
  7. 2013 Medium

    Localized the inter-subunit stabilization function within BLOC-2 to the HPS5 WD40 domain, refining how complex integrity is maintained while confirming HPS3-HPS5-HPS6 binding.

    Evidence In vitro coexpression binding/stability assays with an HPS5 WD40 missense allele and a zebrafish melanosome-biogenesis model

    PMID:23893484

    Open questions at the time
    • HPS3's own contribution to stabilization not mapped to a domain
    • Structural basis of the complex still unresolved
  8. 2018 Medium

    Confirmed in human patients that BLOC-2 integrity depends on all subunits, including HPS3, generalizing the mutual-stabilization model across species.

    Evidence Western blot of partner subunit levels in HPS3/HPS5/HPS6-mutant patient cells identified by NGS

    PMID:30387913

    Open questions at the time
    • Does not add mechanistic detail beyond stability dependence
  9. 2024 Medium

    Elucidated a coat-like mechanism by which BLOC-2 is recruited to endolysosomes through HPS3 to drive WASH recruitment and lysosome maturation.

    Evidence Dictyostelium genetic mutant analysis, WASH localization imaging, live-cell BLOC-2 compartment imaging, and proto-coatomer structural homology modeling

    PMID:39059394

    Open questions at the time
    • Proto-coatomer model is structural prediction, not experimental structure
    • Mechanism of HPS3-mediated endolysosome recruitment not defined at residue level
    • Conservation of the WASH-recruitment role in mammalian melanocytes/platelets untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BLOC-2 recognizes its specific cargo subset and the precise molecular activity (coat versus tether versus adaptor) HPS3 contributes at endolysosomal membranes remain undefined.
  • No experimental structure of BLOC-2 or HPS3
  • Direct cargo-recognition mechanism unproven
  • Biochemical activity of HPS3 not assigned

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CLTCHPS5HPS6
Complex memberships
BLOC-2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HPS3 was identified as a novel gene on chromosome 3q24 encoding a predicted 113.7-kD protein, with a homozygous large deletion (3904-bp founder deletion removing exon 1) causing HPS-3 disease in a genetic isolate of central Puerto Rico, implicating it in vesicle formation in specialized cells. Homozygosity mapping on pooled DNA, gene cloning, mutation analysis Nature genetics Medium 11455388
2003 HPS3 protein was identified as a soluble and membrane-associated protein in HeLa cells; unlike HPS4, HPS3 does NOT associate with HPS1 in the BLOC-3 complex, establishing that HPS3 functions in a distinct complex from HPS1/HPS4. Sedimentation-velocity experiments, coimmunoprecipitation from HeLa cell extracts Proceedings of the National Academy of Sciences of the United States of America Medium 12847290
2004 HPS3, HPS5, and HPS6 proteins form a stable ~340 kDa protein complex called BLOC-2 (Biogenesis of Lysosome-related Organelles Complex-2), demonstrated by coimmunoprecipitation from HeLa cell extracts and by size-exclusion chromatography and density gradient centrifugation. BLOC-2 exists in both a soluble pool and associates with membranes as a peripheral membrane protein. Coimmunoprecipitation, size-exclusion chromatography, density gradient centrifugation Traffic (Copenhagen, Denmark) High 15030569
2004 In mouse tissues, Hps3, Hps5, and Hps6 proteins co-immunoprecipitate and co-sediment in a ~350 kDa complex (BLOC-2). Hps5 protein is destabilized in Hps3 and Hps6 mutant tissues, and Hps6 protein is destabilized in Hps3 and Hps5 mutant tissues, indicating mutual stabilization within BLOC-2. Genetic epistasis (double-mutant mice with identical phenotypes to single mutants) confirms they act within the same pathway for vesicle trafficking to lysosome-related organelles. Coimmunoprecipitation, sucrose gradient sedimentation, gel filtration, Western blot of mutant mouse tissues, double-mutant genetic epistasis analysis The Journal of biological chemistry High 14718540
2005 HPS3 associates with clathrin via a functional clathrin-binding motif (LLDFE at residues 172–176). Clathrin was co-immunoprecipitated by HPS3 antibodies from normal but not HPS3-null melanocytes. GFP-HPS3 co-localizes with clathrin on small vesicles in the perinuclear region during a 20°C temperature block, while a GFP-HPS3 clathrin-binding-domain deletion mutant (GFP-HPS3-delCBD) fails to co-localize with clathrin and shows a largely cytoplasmic distribution. Coimmunoprecipitation from melanocytes, live-cell fluorescence microscopy with temperature block, immunoelectron microscopy, domain deletion mutagenesis BMC cell biology High 16159387
2005 In HPS-3 patient melanocytes, a specific subset of melanocyte proteins — tyrosinase, Tyrp1, Dct, LAMP1, and LAMP3 — show aberrant fine, floccular (rather than coarse granular) distribution, while Silver/Pmel17, Melan-A/MART-1, LAMP2, Rab27, transferrin, c-Kit, adaptin-3, and HPS1 protein localization appears normal, indicating HPS3 selectively controls trafficking of a subset of melanocyte cargo proteins. Immunocytochemistry and confocal microscopy on patient-derived melanocytes, ultrastructural analysis, DOPA histochemistry The American journal of pathology Medium 15632015
2005 In HPS-3 and HPS-1 patient melanocytes, tyrosinase, Tyrp1, and Dct/Tyrp2 are atypically distributed, whereas in HPS-2 melanocytes only tyrosinase shows atypical distribution. In HPS-3 melanocytes, LAMP1 and LAMP3 show a distinct less granular, more floccular pattern; HPS3 melanocytes express normal HPS1 and AP3B1 proteins. Immunofluorescence microscopy on patient-derived melanocytes, Western blot The Journal of investigative dermatology Medium 15675963
2009 Functional deletion of HPS3 (HPS3−/− mice) markedly reduces platelet dense-granule secretion without affecting platelet counts, platelet morphology, alpha-granule number, or maximal P-selectin secretion. HPS3-deficient mice show significantly reduced capacity to form platelet-leukocyte aggregates, and are completely resistant to thrombotic arterial occlusion after FeCl3 injury, demonstrating HPS3's specific role in dense-granule biogenesis/secretion. Mouse knockout model, platelet function assays, flow cytometry, in vivo carotid artery thrombosis model Circulation High 19687360
2013 In zebrafish, an Hps5 missense mutation (hps5I76N) within the N-terminal WD40 repeat domain disrupts melanosome biogenesis; in vitro coexpression assays show that Hps5I76N retains the ability to bind its BLOC-2 complex partners Hps3 and Hps6, but the mutual stabilization between Hps5 and Hps6 is disrupted by this allele, establishing that the WD40 domain of Hps5 is important for inter-subunit stabilization within BLOC-2. In vitro coexpression binding assay, Western blot for protein stability, zebrafish genetic model Genetics Medium 23893484
2018 In Chinese HPS patients with mutations in HPS3 (as well as HPS5, HPS6), the respective partner subunits of BLOC-2 are destabilized, confirming that BLOC-2 integrity depends on all its subunits including HPS3. Western blot of patient-derived cells after NGS-identified mutations Pigment cell & melanoma research Medium 30387913
2024 BLOC-2 (containing HPS3, HPS5, HPS6 and a fourth Claret-ortholog subunit) is recruited to endolysosomes via its HPS3 subunit in Dictyostelium. In BLOC-2 mutants, WASH complex recruitment is inefficient, causing failure of lysosome maturation. Structural modeling suggests all four BLOC-2 subunits are proto-coatomer proteins, indicating BLOC-2 acts as a coat-like complex at endolysosomes. Dictyostelium genetic mutant analysis, WASH localization imaging, structural homology modeling, live-cell imaging of BLOC-2 compartment localization Current biology : CB Medium 39059394

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nature genetics 166 11455388
2002 Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nature genetics 147 11836498
2003 Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4. Proceedings of the National Academy of Sciences of the United States of America 107 12847290
2003 Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Human genetics 106 12664304
2004 Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6. Traffic (Copenhagen, Denmark) 87 15030569
2002 Hermansky-Pudlak syndrome: vesicle formation from yeast to man. Pigment cell research 84 12453182
2002 Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Current molecular medicine 75 12125811
2001 Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. American journal of human genetics 68 11590544
2004 The Hermansky-Pudlak syndrome 3 (cocoa) protein is a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). The Journal of biological chemistry 66 14718540
2009 Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. Circulation 57 19687360
2009 Genetic determinants of hair and eye colours in the Scottish and Danish populations. BMC genetics 50 20042077
2002 Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases. Human mutation 49 12442288
2006 Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico. The Journal of investigative dermatology 47 16417222
2005 Melanocytes derived from patients with Hermansky-Pudlak Syndrome types 1, 2, and 3 have distinct defects in cargo trafficking. The Journal of investigative dermatology 47 15675963
2004 Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex. Blood 43 15265785
2009 Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6. Journal of medical genetics 39 19843503
2005 Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3. The American journal of pathology 36 15632015
2007 Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5. The Journal of investigative dermatology 34 17301833
2019 NGS-based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism. Pigment cell & melanoma research 30 31141302
2016 NGS-based 100-gene panel of hypopigmentation identifies mutations in Chinese Hermansky-Pudlak syndrome patients. Pigment cell & melanoma research 29 27593200
2004 Hermansky-Pudlak syndrome type 4 in a patient from Sri Lanka with pulmonary fibrosis. American journal of medical genetics. Part A 29 15108212
2013 snow white, a zebrafish model of Hermansky-Pudlak Syndrome type 5. Genetics 26 23893484
2020 Current landscape of Oculocutaneous Albinism in Japan. Pigment cell & melanoma research 25 32969595
2010 Antidiabetic properties of purified polysaccharide from Hedysarum polybotrys. Canadian journal of physiology and pharmacology 24 20130740
2021 A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules. Blood 21 33513603
2021 Inflammatory bowel disease in Hermansky-Pudlak syndrome: a retrospective single-centre cohort study. Journal of internal medicine 20 33423334
2006 A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics. Human mutation 19 17041891
2018 Instability of BLOC-2 and BLOC-3 in Chinese patients with Hermansky-Pudlak syndrome. Pigment cell & melanoma research 18 30387913
2005 Association of the Hermansky-Pudlak syndrome type-3 protein with clathrin. BMC cell biology 15 16159387
2020 Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia. PloS one 14 32502225
2020 Genetic variants and mutational spectrum of Chinese Hermansky-Pudlak syndrome patients. Pigment cell & melanoma research 14 32725903
2014 Structural characterization and stimulating effect on osteoblast differentiation of a purified heteropolysaccharide isolated from Hedysarum polybotrys. Carbohydrate polymers 14 25037407
2024 Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Journal of cardiovascular development and disease 13 38786974
2022 Triphenyltin exposure induced abnormal morphological colouration in adult male guppies (Poecilia reticulata). Ecotoxicology and environmental safety 13 35905627
2017 Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS. Pigment cell & melanoma research 13 28640947
2021 Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism. Genes 12 33808351
2017 Novel mutation in two brothers with Hermansky Pudlak syndrome type 3. Blood cells, molecules & diseases 11 28284561
2007 A large analphoid invdup(3)(q22.3qter) marker chromosome characterized by array-CGH in a child with malformations, mental retardation, ambiguous genitalia and Blaschko's lines. European journal of medical genetics 11 17567547
2023 Report of Hermansky-Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes. Genes 10 36672886
2022 Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7). Frontiers in pharmacology 10 35126127
2023 Targeted long-read sequencing identifies and characterizes structural variants in cases of inherited platelet disorders. Journal of thrombosis and haemostasis : JTH 9 38007062
2019 Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report. BMC pulmonary medicine 9 31619213
2017 Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5. PloS one 9 28296950
2010 Newborn screening for hermansky-pudlak syndrome type 3 in Puerto Rico. Journal of pediatric hematology/oncology 8 20562649
2020 Novel Brown Coat Color (Cocoa) in French Bulldogs Results from a Nonsense Variant in HPS3. Genes 7 32526956
2014 Ocular Findings in Patients with the Hermansky-Pudlak Syndrome (Types 1 and 3). Ophthalmic genetics 7 24766090
2024 Biogenesis of lysosome-related organelles complex-2 is an evolutionarily ancient proto-coatomer complex. Current biology : CB 5 39059394
2023 High-throughput microfluidic blood testing to phenotype genetically linked platelet disorders: an aid to diagnosis. Blood advances 5 37389831
2019 Bleeding assessment in female patients with the Hermansky-Pudlak syndrome-A case series. European journal of haematology 4 30659653
2022 NGS-based targeted sequencing identified two novel variants in Southwestern Chinese families with oculocutaneous albinism. BMC genomics 3 35488210
2019 Novel variant in HPS3 gene in a patient with Hermansky Pudlak syndrome (HPS) type 3. Platelets 3 31880485
2018 [Molecular analysis of gene mutations in eight patients with Glanzmann's thrombasthenia]. Zhonghua yi xue za zhi 3 30138987
2001 Characterization of the murine gene corresponding to human Hermansky-Pudlak syndrome type 3: exclusion of the Subtle gray (sut) locus. Molecular genetics and metabolism 3 11592818
2024 Genetic screening reveals hotspot variants and prevalence rates of Hermansky-Pudlak syndrome in the Chinese population. Clinica chimica acta; international journal of clinical chemistry 2 38876249
2022 Oculocutaneous albinism and bleeding diathesis due to a novel deletion in the HPS3 gene. Frontiers in genetics 2 36046236
2021 Whole-Exome Sequencing Identified a Novel Homozygous Frameshift Mutation of HPS3 in a Consanguineous Family with Hermansky-Pudlak Syndrome. BioMed research international 2 34608437
2017 Genetic variants and phylogenetic analysis of Haemophilus parasuis (HPS) OMPP2 detected in Sichuan, China from 2013 to 2015. The Journal of veterinary medical science 2 28824043
2009 Identifying putative promoter regions of Hermansky-Pudlak syndrome genes by means of phylogenetic footprinting. Annals of human genetics 2 19523149
2025 Exome and Genome Sequencing Reveals Novel Variants for Severe Diabetic Retinopathy in Type 1 Diabetes. Investigative ophthalmology & visual science 0 41129127
2025 A novel HPS3 pathogenic nonsense variant associated with Hermansky-Pudlak syndrome type 3 and a platelet dysfunction. Molecular biology reports 0 41196426
2024 Genomic analysis links the American mink Royal pastel coat phenotype to retroviral element type 1 insertion in the HPS3 gene. Animal genetics 0 38956930
2024 After an initial Hermansky-Pudlak syndrome clinical diagnosis, molecular testing reveals variants for oculocutaneous albinism type 1B: A case report. Molecular genetics & genomic medicine 0 38994739

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