Engulfment and cell motility protein 1 is a protein that in humans is encoded by the ELMO1gene.[1][2] ELMO1 is located on chromosome number seven in humans and is located on chromosome number thirteen in mice.
ELMO1 also has a pro-rich motif at the extreme C terminus. Secondary structure analysis has predicted that there are alpha-helical regions at both the N and C-terminus.[3]
The structure of the pleckstrin homology domain of ELMO1 has been determine by X-ray crystallography.[3]
Function
The protein encoded by this gene interacts with the dedicator of cyto-kinesis 1 protein to promote phagocytosis and effect cell shape changes. Similarity to a C. elegans protein suggests that this protein may function in apoptosis and in cell migration. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.[2]
Interactions
ELMO1 has been shown to interact with Dock180[1][4] and HCK. ELMO1 directly interacts with the SH3 domain of HCK. The association between ELMO1 and HCK is dependent on polyproline interactions.[5]
When ELMO1 is complexed with DOCK180, Rac GTPase-dependent biological processes are activated. The pH domain of ELMO1 functions in trans to stabilize DOCK180 and make it resistant to degradation. When ELMO1 binds to DOCK180 it relieves the steric inhibition of DOCK180 which then activates the Rac GTPase. The pro-rich motif of the C terminus on ELMO1 is essential for the binding of ELMO1 to the SH3 domain at the N terminus of DOCK180.[3] The complex of ELMO1 and DOCK180 act as a regulator of Rac during development of a cell and cell migration. Mutation of both interaction sites for DOCK180 on ELMO1 will lead to the disruption of the ELMO1-DOCK180 complex. ELMO1 complexed with both DOCK180 and CrkII leads to maximal efficiency of phagocytosis in the cell. This complex of molecules happens upstream of Rac during phagocytosis.[1]
References
↑ 1.01.11.2Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS (Oct 2001). "CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration". Cell. 107 (1): 27–41. doi:10.1016/S0092-8674(01)00520-7. PMID11595183.
↑Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS (August 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex". Nat. Cell Biol. 4 (8): 574–82. doi:10.1038/ncb824. PMID12134158.
↑Scott MP, Zappacosta F, Kim EY, Annan RS, Miller WT (August 2002). "Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1". J. Biol. Chem. 277 (31): 28238–46. doi:10.1074/jbc.M202783200. PMID12029088.
Further reading
Ohara O, Nagase T, Ishikawa K, et al. (1997). "Construction and characterization of human brain cDNA libraries suitable for analysis of cDNA clones encoding relatively large proteins". DNA Res. 4 (1): 53–9. doi:10.1093/dnares/4.1.53. PMID9179496.
Scott MP, Zappacosta F, Kim EY, et al. (2002). "Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1". J. Biol. Chem. 277 (31): 28238–46. doi:10.1074/jbc.M202783200. PMID12029088.
Brugnera E, Haney L, Grimsley C, et al. (2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex". Nat. Cell Biol. 4 (8): 574–82. doi:10.1038/ncb824. PMID12134158.
Sanui T, Inayoshi A, Noda M, et al. (2003). "DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1". Blood. 102 (8): 2948–50. doi:10.1182/blood-2003-01-0173. PMID12829596.
Katoh H, Negishi M (2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature. 424 (6947): 461–4. doi:10.1038/nature01817. PMID12879077.
Grimsley CM, Kinchen JM, Tosello-Trampont AC, et al. (2004). "Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration". J. Biol. Chem. 279 (7): 6087–97. doi:10.1074/jbc.M307087200. PMID14638695.
Wang X, Wu YC, Fadok VA, et al. (2003). "Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12". Science. 302 (5650): 1563–6. doi:10.1126/science.1087641. PMID14645848.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nat. Struct. Mol. Biol. 11 (8): 756–62. doi:10.1038/nsmb800. PMID15247908.
deBakker CD, Haney LB, Kinchen JM, et al. (2005). "Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO". Curr. Biol. 14 (24): 2208–16. doi:10.1016/j.cub.2004.12.029. PMID15620647.
Akakura S, Kar B, Singh S, et al. (2005). "C-terminal SH3 domain of CrkII regulates the assembly and function of the DOCK180/ELMO Rac-GEF". J. Cell. Physiol. 204 (1): 344–51. doi:10.1002/jcp.20288. PMID15700267.
Lu M, Kinchen JM, Rossman KL, et al. (2005). "A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs". Curr. Biol. 15 (4): 371–7. doi:10.1016/j.cub.2005.01.050. PMID15723800.
Shimazaki A, Kawamura Y, Kanazawa A, et al. (2005). "Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy". Diabetes. 54 (4): 1171–8. doi:10.2337/diabetes.54.4.1171. PMID15793258.
