IMD domain

In molecular biology, the IMD domain (IRSp53 and MIM (missing in metastases) homology Domain) is a BAR-like domain of approximately 250 amino acids found at the N-terminus in the insulin receptor tyrosine kinase substrate p53 (IRSp53/BAIAP2) and in the evolutionarily related IRSp53/MIM (MTSS1) family. In IRSp53, a ubiquitous regulator of the actin cytoskeleton, the IMD domain acts as conserved F-actin bundling domain involved in filopodium formation. Filopodium-inducing IMD activity is regulated by Cdc42 and Rac1 (Rho-family GTPases) and is SH3-independent.^[1][2][3] The IRSp53/MIM family is a novel F-actin bundling protein family that includes invertebrate relatives:

• Vertebrate MIM (missing in metastasis) (MTSS1), an actin-binding scaffold protein that may be involved in cancer metastasis.
• Vertebrate ABBA-1 (MTSS1L), a MIM-related protein.
• Vertebrate brain-specific angiogenesis inhibitor 1-associated protein 2 (BAI1-associated protein 2) or insulin receptor tyrosine kinase substrate p53 (IRSp53), a multifunctional adaptor protein that links Rac1 with a Wiskott–Aldrich syndrome family verprolin-homologous protein 2 (WAVE2/WASF2) to induce lamellipodia or Cdc42 with Mena to induce filopodia.^[4]
• Vertebrate brain-specific angiogenesis inhibitor 1-associated protein 2-like proteins 1 and 2 (BAI1-associated protein 2-like proteins 1 and 2, BAIAP2L1 and BAIAP2L2).
• Drosophila melanogaster (Fruit fly) CG32082-PA.
• Caenorhabditis elegans M04F3.5 protein.

IRSp53/MIM homology domain
crystal structure of rcb domain of irsp53
Identifiers
Symbol	IMD
Pfam	PF08397
Pfam clan	CL0145
InterPro	IPR013606
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

The vertebrate IRSp53/MIM family is divided into two major groups: the IRSp53 subfamily and the MIM/ABBA subfamily. The putative invertebrate homologues are positioned between them. The IRSp53 subfamily members contain an SH3 domain, and the MIM/ABBA subfamily proteins contain a WH2 (WASP-homology 2) domain. The vertebrate SH3-containing subfamily is further divided into three groups according to the presence or absence of the WWB and the half-CRIB motif. The IMD domain can bind to and bundle actin filaments, bind to membranes and interact with the small GTPase Rac.^[1][5]

The IMD domain folds as a coiled coil of three extended alpha-helices and a shorter C-terminal helix. Helix 4 packs tightly against the other three helices, and thus represents an integral part of the domain. The fold of the IMD domain closely resembles that of the BAR (Bin-Amphiphysin-RVS) domain, a functional module serving both as a sensor and inducer of membrane curvature.^[3] The IMD domain is also known as the I-BAR domain because of its inverse curvature of the membrane binding surface compared to that of the BAR domain. The WH2 domain performs a scaffolding function.^[6]

References

1. Yamagishi A, Masuda M, Ohki T, Onishi H, Mochizuki N (April 2004). "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein". J. Biol. Chem. 279 (15): 14929–36. doi:10.1074/jbc.M309408200. PMID 14752106.
2. Millard TH, Dawson J, Machesky LM (May 2007). "Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties". J. Cell Sci. 120 (Pt 9): 1663–72. doi:10.1242/jcs.001776. PMID 17430976. S2CID 39973979.
3. Millard TH, Bompard G, Heung MY, Dafforn TR, Scott DJ, Machesky LM, Fütterer K (January 2005). "Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53". EMBO J. 24 (2): 240–50. doi:10.1038/sj.emboj.7600535. PMC 545821. PMID 15635447.
4. Koh JT, Kook H, Kee HJ, Seo YW, Jeong BC, Lee JH, Kim MY, Yoon KC, Jung S, Kim KK (March 2004). "Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking alphavbeta5 integrin". Exp. Cell Res. 294 (1): 172–84. doi:10.1016/j.yexcr.2003.11.008. PMID 14980512.
5. Machesky LM, Johnston SA (June 2007). "MIM: a multifunctional scaffold protein". J. Mol. Med. 85 (6): 569–76. doi:10.1007/s00109-007-0207-0. PMID 17497115. S2CID 32096007.
6. Lee SH, Kerff F, Chereau D, Ferron F, Klug A, Dominguez R (February 2007). "Structural basis for the actin-binding function of missing-in-metastasis". Structure. 15 (2): 145–55. doi:10.1016/j.str.2006.12.005. PMC 1853380. PMID 17292833.

This article incorporates text from the public domain Pfam and InterPro: IPR013606