IMD domain explained

Symbol:	IMD
IRSp53/MIM homology domain
Pfam:	PF08397
Pfam Clan:	CL0145
Interpro:	IPR013606

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.

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]

Notes and References

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