FGD1
FGD1 | |||
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Identifiers | |||
Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
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RefSeq (protein) | |||||||||
Location (UCSC) | Chr X: 54.45 – 54.5 Mb | Chr X: 149.83 – 149.87 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF) is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome.[5] Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans.[6] It is a member of the FYVE, RhoGEF and PH domain containing family.
FGD1 is a
The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities.
Structure
The mature human protein contains several characteristic motifs and domains that are involved in the protein's function. The 961 amino acid long protein has an approximate size of 106kDa. The N-terminal is a proline-rich stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, stretches from amino acid 7 – 330, followed by a
The DH domain is required for the activation of Cdc42, through the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1.[7][13] FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.[14]
Function
FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to Golgi membranes. Levels of both FGD1 and Cdc42 are enriched on the Golgi complex itself and their interdependence regulates the transport of cargo proteins from the Golgi. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport.[7] Another interaction partner of FGD1 is cortactin, which is directly bound by the proline-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex, this interaction seems to promote actin assembly.[11]
FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.[13]
Tissue distribution
Human FGD1 is expressed predominantly in fetal tissues of brain and kidney, but also present in the heart and lung. It is hardly detectable in the corresponding adult tissues. FGD1 is expressed in areas of bone formation and post-natally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.[5][7]
Clinical significance
Mutations in the FGD1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also known as
The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1.[12][15][16][17] Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).[18]
Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.[13]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000102302 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025265 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 9593458.
- PMID 11751687.
- ^ PMID 19261807.
- ^ PMID 8994827.
- PMID 9624130.
- PMID 9671479.
- ^ PMID 15020669.
- ^ S2CID 23180550.
- ^ PMID 19141649.
- PMID 11181572.
- PMID 19110080.
- PMID 14560308.
- PMID 11093277.
- S2CID 21317320.