Pleckstrin

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Pleckstrin-1
2I5C pleckstrin.png
Ribbon diagram of the C-terminal pleckstrin homology domain of pleckstrin-1 bound to inositol 1,2,3,4,5-pentaphosphate (PDB ID 2I5C)
Identifiers
SymbolPLEK
NCBI gene 5341
HGNC 9070
OMIM 173570
RefSeq NM_002664
UniProt P08567
Other data
Locus Chr. 2 p13.3
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Structures Swiss-model
Domains InterPro
Pleckstrin-2
Identifiers
SymbolPLEK2
NCBI gene 26499
HGNC 19238
OMIM 608007
PDB 1X1G
RefSeq NM_016445
UniProt Q9NYT0
Other data
Locus Chr. 14 q23.3q24.1
Wikidata Q18038260
Search for
Structures Swiss-model
Domains InterPro

Pleckstrins are a family of proteins found in platelets [1] and other cells. The name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. The prototype protein, now called pleckstrin-1, was first identified in 1979 as the major substrate of protein kinase C in platelets. [2] The homolog pleckstrin-2 is more widely expressed in tissues. [3]

Contents

The pleckstrin homology domain (PH domain) was named after pleckstrin-1. [2]

Sequence and structure

Both pleckstrin-1 and pleckstrin-2 contain two pleckstrin homology domains, separated by a central dishevelled-Egl10-pleckstrin (DEP) domain. Pleckstrin-1 is phosphorylated by protein kinase C on three serine and threonine residues located between the first pleckstrin homology domain and the DEP domain; [2] pleckstrin-2 is not a substrate for protein kinase C. [2] [4] The two proteins share 65% sequence homology [2] and have a size of about 47 kilodaltons. [5]

As of 2024, no high-resolution three-dimensional structure has been solved for full-length pleckstrin, but the structures of the individual domains of both pleckstrin-1 and -2 have been published. [2]

Functions

Pleckstrins are involved in rearranging the actin cytoskeleton in such processes as platelet activation, erythropoeisis, and cell spreading by extension of filopodia and lamellipodia. [3] Pleckstrin-1 is believed to become activated by protein kinase C phosphorylation, which results in binding of the membrane lipid phosphatidylinositol 3,4-bisphosphate. [2] Interactions with integrins and the Rac GTPase then lead to reorganization of the actin cytoskeleton. [3] Pleckstrin-2 also binds to inositol phospholipids, but interacts directly with F-actin, unlike pleckstrin-1. [3] Since pleckstrin-2 is expressed in a wider variety of cell types, its biological roles are more diverse than those of pleckstrin-1.

Pleckstrin-1 is a key protein in the membrane remodelling processes that occur during platelet activation. [2] It also occurs in immune cells such as macrophages and neutrophils, [2] [3] where it is involved in formation of phagosomes and the secretion of proinflammatory cytokines. [3]

Pleckstrin-2 has roles in cell spreading, inflammation, erythropoeisis, and tumorigenesis. In lymphocytes, it is involved in PI3 kinase-mediated immune synapse formation. Pleckstrin-2 also mediates cytoskeletal changes involved in proliferation of erythroblasts early in erythropoeisis. It is also believed to be crucial in the epithelial-to-mesenchymal transition in tumor metastasis, and pleckstrin-2 is known to be overexpressed in a variety of cancers. [3]

Related Research Articles

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Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

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<span class="mw-page-title-main">Pleckstrin homology domain</span> Protein domain

Pleckstrin homology domain or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.

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<span class="mw-page-title-main">ROCK1</span> Protein

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<span class="mw-page-title-main">INPP5D</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

<span class="mw-page-title-main">PLEKHO1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PLEKHA1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SH2B3</span> Protein-coding gene in the species Homo sapiens

SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12. SH2B3 is ubiquitously expressed in many tissues and cell types. LNK functions as a regulator in signaling pathways relating to hematopoiesis, inflammation, and cell migration. As a result, it is involved in blood diseases, autoimmune disorders, and vascular disease. The SH2B3 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">PLEK2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ERM protein family</span> Protein family

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<span class="mw-page-title-main">Phosphoinositide-dependent kinase-1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Rho-associated protein kinase</span>

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References

  1. Harlan JE, Hajduk PJ, Yoon HS, Fesik SW (September 1994). "Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate". Nature. 371 (6493): 168–170. Bibcode:1994Natur.371..168H. doi:10.1038/371168a0. hdl: 10356/94313 . PMID   8072546. S2CID   4321763.
  2. 1 2 3 4 5 6 7 8 9 Edlich C, Stier G, Simon B, Sattler M, Muhle-Goll C (February 2005). "Structure and phosphatidylinositol-(3,4)-bisphosphate binding of the C-terminal PH domain of human pleckstrin". Structure. 13 (2): 277–286. doi: 10.1016/j.str.2004.11.012 . PMID   15698571.
  3. 1 2 3 4 5 6 7 Wang G, Zhou Q, Xu Y, Zhao B (2021). "Emerging Roles of Pleckstrin-2 Beyond Cell Spreading". Frontiers in Cell and Developmental Biology. 9: 768238. doi: 10.3389/fcell.2021.768238 . PMC   8637889 . PMID   34869363.
  4. Hu MH, Bauman EM, Roll RL, Yeilding N, Abrams CS (July 30, 1999). "Pleckstrin 2, a widely expressed paralog of pleckstrin involved in actin rearrangement". J Biol Chem. 274 (31): 21515–21518. doi: 10.1074/jbc.274.31.21515 . PMID   10419454.
  5. "PLEK - Pleckstrin - Homo sapiens (Human)". Uniprot. EMBI-EBL. Retrieved 18 Mar 2024.