Phosphatidylinositol-binding clathrin assembly protein (PICALM)

The protein contains 652 amino acids for an estimated molecular weight of 70755 Da.

 

Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells. Recruits AP-2 and attaches clathrin triskelions to the cytoplasmic side of plasma membrane leading to clathrin-coated vesicles (CCVs) assembly (PubMed:10436022, PubMed:16262731, PubMed:27574975). Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature (PubMed:25898166). In addition to binding to clathrin, mediates the endocytosis of small R-SNARES (Soluble NSF Attachment Protein REceptors) between plasma membranes and endosomes including VAMP2, VAMP3, VAMP4, VAMP7 or VAMP8 (PubMed:22118466, PubMed:21808019, PubMed:23741335). In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors (PubMed:25241929). Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF) (PubMed:25241929, PubMed:24067654). (updated: Feb. 13, 2019)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  3. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  6. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.


Interpro domains
Total structural coverage: 46%
Model score: 0
No model available.

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VariantDescription
dbSNP:rs12800974
dbSNP:rs12222608
dbSNP:rs1043858
dbSNP:rs1043859
dbSNP:rs556337

Biological Process

Amyloid-beta clearance by transcytosis GO Logo
Axonogenesis GO Logo
Cell population proliferation GO Logo
Clathrin coat assembly GO Logo
Clathrin-coated pit assembly GO Logo
Clathrin-dependent endocytosis GO Logo
Dendrite morphogenesis GO Logo
Endocytosis GO Logo
Endosomal transport GO Logo
Hemopoiesis GO Logo
Iron ion homeostasis GO Logo
Iron ion import across plasma membrane GO Logo
Iron ion import into cell GO Logo
Learning or memory GO Logo
Membrane bending GO Logo
Membrane organization GO Logo
Modulation of age-related behavioral decline GO Logo
Negative regulation of gene expression GO Logo
Negative regulation of metalloendopeptidase activity involved in amyloid precursor protein catabolic process GO Logo
Negative regulation of protein localization to cell surface GO Logo
Negative regulation of protein localization to plasma membrane GO Logo
Negative regulation of receptor-mediated endocytosis GO Logo
Positive regulation of amyloid-beta clearance GO Logo
Positive regulation of amyloid-beta formation GO Logo
Positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process GO Logo
Positive regulation of clathrin-dependent endocytosis GO Logo
Positive regulation of GTPase activity GO Logo
Positive regulation of neuron death GO Logo
Positive regulation of transcription, DNA-templated GO Logo
Protein complex assembly GO Logo
Protein-containing complex assembly GO Logo
Receptor internalization GO Logo
Receptor-mediated endocytosis GO Logo
Regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process GO Logo
Regulation of endocytosis GO Logo
Regulation of protein localization GO Logo
Regulation of vesicle size GO Logo
Synaptic vesicle budding from presynaptic endocytic zone membrane GO Logo
Synaptic vesicle endocytosis GO Logo
Synaptic vesicle maturation GO Logo
Transcytosis GO Logo
Vesicle budding from membrane GO Logo
Vesicle cargo loading GO Logo
Vesicle organization GO Logo
Vesicle-mediated transport GO Logo

The reference OMIM entry for this protein is 603025

Phosphatidylinositol-binding clathrin assembly protein; picalm
Clathrin assembly lymphoid-myeloid leukemia gene; calm
Clth
Lap, drosophila, homolog of; lap picalm/af10 fusion gene, included

DESCRIPTION

PICALM is involved in cellular trafficking, regulation of endocytosis, and clathrin-mediated vesicle formation. It is tightly associated with iron homeostasis and cell proliferation, and these processes are strongly tied to embryonic development (summary by Stern et al., 2014).

CLONING

By screening a U937 human monocytoma cDNA library, Dreyling et al. (1996) cloned PICALM, which they called CALM. The deduced protein contains 652 amino acids. Northern blot analysis detected variable expression of a major transcript of approximately 4 kb in all human tissues and cell lines examined. Minor transcripts of approximately 9 and 3 kb were also detected in testis. Zoo blot analysis revealed orthologs of CALM in all mammals examined and in chicken. Database analysis extended conservation of Calm to yeast, with highest homology in the N-terminal 300 amino acids. CALM shares significant homology with the murine clathrin assembly protein ap3 (SNAP91; 607923) (Morris et al., 1993).

MAPPING

By sequence and somatic cell hybrid analyses, Dreyling et al. (1996) mapped the PICALM gene to chromosome 11q14.

BIOCHEMICAL FEATURES

Ford et al. (2001) presented the structure of the N-terminal domain of CALM bound to phosphatidylinositol-4,5-bisphosphate via a lysine-rich motif. This motif is found in other proteins predicted to have domains of similar structure (e.g., Huntingtin-interacting protein-1; 601767). The structure is in part similar to the epsin (607262) N-terminal (ENTH) domain, but epsin lacks the phosphatidylinositol-4,5-bisphosphate-binding site. Mao et al. (2001) determined the crystal structure of the N-terminal domain (the NAP domain) of the Drosophila Lap protein, which is homologous to human PICALM. The structure revealed a novel fold consisting of a large double layer of sheets of 10 alpha helices and a unique site for binding phosphoinositides.

CYTOGENETICS

- PICALM/AF10 Fusion Gene Dreyling et al. (1996) identified a breakpoint on chromosome 11 involving the CALM gene in the translocation t(10;11)(p13;q14) in the monocytic cell line U937. The fusion partner of the CALM gene on chromosome 11 was the putative transcription factor AF10 (602409) located on 10p13. Dreyling et al. (1998) found that both MLL (159555) and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with t(10;11). Both rearrangements were associated with a poor prognosis. Bohlander et al. (2000) and Carlson et al. (2000) performed molecular analyses of the CALM/AF10 fusion in cases of leukemia. Bohlander et al. (2000) studied a series of 3 patients with AML, 1 patient with T-ALL, and 2 patients with precursor T lymphoblastic lymphoma. The rearrangements were essentially identical in all. In all 6 patients the breakpoint in CALM was at the 3-prime end of the coding region. Three breakpoints could be identified in AF10. The findings indicated that CALM/AF10 fusions differ only slightly with respect to the portion of AF10 present and that there is no obvious difference between the fusions found in AML patients compared to those found in patients with lymphoid malignancies. Carlson et al. (2000) studied 6 patients with myeloid leukemia and 3 with T-cell lymphoblastic leukemia. They identified 4 different CALM/AF10 fusion products in 5 patients and AF10/CALM reciprocal message in 1. Carlson et al. (2000) concluded that the fusion of CALM and AF10 is a recurring abnormality in both lymphoid ... More on the omim web site

Subscribe to this protein entry history

Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603025 was added.