Phospholipid scramblase 1 (PLSCR1)

The protein contains 318 amino acids for an estimated molecular weight of 35049 Da.

 

Catalyzes calcium-induced ATP-independent rapid bidirectional and non-specific movement of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane resulting in collapse of the phospholipid asymmetry which leads to phosphatidylserine externalization on the cell surface (PubMed:9218461, PubMed:8663431, PubMed:10770950, PubMed:9572851, PubMed:9485382, PubMed:18629440, PubMed:23590222, PubMed:24648509, PubMed:24343571, PubMed:32110987, PubMed:23659204, PubMed:29748552). Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with TRPC5 (By similarity). Also exhibits magnesium-dependent nuclease activity against double-stranded DNA and RNA but not single-stranded DNA and can enhance DNA decatenation mediated by TOP2A (PubMed:27206388, PubMed:17567603). Negatively regulates FcR-mediated phagocytosis in differentiated macrophages (PubMed:26745724). May contribute to cytokine-regulated cell proliferation and differentiation (By similarity). May play a role in the antiviral response of interferon (IFN) by amplifying and enhancing the IFN response through increased expression of select subset of potent antiviral genes (PubMed:15308695). Acts as an attachment receptor for HCV (PubMed:21806988). (updated: Feb. 10, 2021)

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. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. 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.
  4. 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.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. 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.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.

Topcons

Interpro domains
Total structural coverage: 99%
Model score: 0
MODL_ROSETTA-3.4
MODL_I-TASSER-3.0

(right-click above to access to more options from the contextual menu)

VariantDescription
dbSNP:rs343320

The reference OMIM entry for this protein is 604170

Phospholipid scramblase 1; plscr1
Mm1 cell-derived transplantability-associated gene 1b, mouse, homolog of; mmtra1b

CLONING

The plasma membrane phospholipids (PLs) are normally asymmetrically distributed, with phosphatidylcholine (PC) and sphingomyelin located primarily in the outer leaflet and the aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine restricted to the cytoplasmic leaflet. An increase in intracellular calcium due to cell activation, cell injury, or apoptosis causes a rapid bidirectional movement of the plasma membrane PLs between leaflets, resulting in exposure of PS and phosphatidylethanolamine at the cell surface. This movement is thought to play a key role in expression of platelet procoagulant activity and in clearance of injured or apoptotic cells. Basse et al. (1996) purified PL scramblase, a 37-kD plasma membrane protein that mediates accelerated transbilayer migration of phospholipids upon binding calcium ions. By searching an EST database with the partial protein sequence of PL scramblase, Zhou et al. (1997) identified a partial human cDNA. They used the partial cDNA to screen a human leukemic cell library and isolated cDNAs corresponding to the entire PL scramblase coding region. The predicted protein contains 318 amino acids and has a pI of 4.8. Sequence analysis suggested that PL scramblase is a type II plasma membrane protein, with a long N-terminal cytoplasmic domain, a transmembrane region, and a short extracellular tail. The authors noted that this topology is consistent with the anticipated topology of PL scramblase in the erythrocyte membrane, where lipid-mobilizing function is in response to calcium only at the cytoplasmic surface of the membrane. Using Northern blot analysis, the authors demonstrated that PL scramblase was expressed as 1.6- and 2.6-kb mRNAs in all tissues and cell lines tested. Independently, Kasukabe et al. (1998) identified PL scramblase as the human homolog of mouse MmTRA1b (Mm1 cell-derived transplantability-associated gene 1b), the gene encoding a truncated leukemogenesis-associated cDNA, MmTRA1a. Human and mouse MmTRA1b are 78% identical. Sequence analysis revealed that the predicted human protein contains 3 leucine repeats and a proline-rich N-terminal domain with 3 motifs which may act as docking sites for SH3 motifs. Kasukabe et al. (1998) noted that mouse MmTRA1b was distinct from a putative mouse PL scramblase homolog identified by Zhou et al. (1998). The mouse protein described by Zhou et al. (1998) shares 75% and 71% identity with mouse MmTRA1b and human PL scramblase, respectively.

GENE FUNCTION

Zhou et al. (1997) showed that recombinant PL scramblase exhibited calcium-dependent PL scramblase activity in vitro. Quantitative immunoblotting revealed that PL scramblase levels are approximately 10-fold higher in platelets than in erythrocytes, which Zhou et al. (1997) stated was consistent with the apparent increased enzyme activity of the platelet plasma membrane. By yeast 2-hybrid analysis, Kametaka et al. (2003) found that the cytoplasmic domain of PLSCR1 interacted with BACE1 (604252), a proteinase responsible for beta-site processing of amyloid precursor protein (APP; 104760). Mutation analysis indicated that a dileucine motif in the C-terminal tail of BACE1 was required for BACE1-PLSCR1 interaction. BACE1 and PLSCR1 colocalized in the Golgi area and in endosomal compartments, and inhibition of intracellular membrane trafficking showed that both proteins share a common trafficking pathway. Coimmunoprecipitation analysis identified an endogenou ... More on the omim web site

Subscribe to this protein entry history

Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

May 12, 2019: Protein entry updated
Automatic update: model status changed

Nov. 17, 2018: Protein entry updated
Automatic update: model status changed

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

Oct. 27, 2017: Protein entry updated
Automatic update: model status changed

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 604170 was added.

Jan. 25, 2016: Protein entry updated
Automatic update: model status changed