IMD domain

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IRSp53/MIM homology domain
PDB 1wdz EBI.jpg
crystal structure of rcb domain of irsp53
Identifiers
SymbolIMD
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:

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]

Related Research Articles

Insulin receptor Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

GRB2

Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

Ena/Vasp homology proteins

ENA/VASP homology proteins or EVH proteins are a family of closely related proteins involved in cell motility in vertebrate and invertebrate animals. EVH proteins are modular proteins that are involved in actin polymerization, as well as interactions with other proteins. Within the cell, Ena/VASP proteins are found at the leading edge of Lamellipodia and at the tips of filopodia. Ena, the founding member of the family was discovered in a drosophila genetic screen for mutations that act as dominant suppressors of the abl non receptor tyrosine kinase. Invertebrate animals have one Ena homologue, whereas mammals have three, named Mena, VASP, and Evl.

Adapter molecule crk

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

Fascin

Fascin is an actin bundling protein.

GRB10

Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.

CDC42 Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog, also known as Cdc42, is a protein involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

IRS1

Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the IRS-1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.

WASF2

Wiskott-Aldrich syndrome protein family member 2 is a protein that in humans is encoded by the WASF2 gene.

NCK1

Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.

INPPL1

SH2-domain containing Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 is an enzyme that in humans is encoded by the INPPL1 gene.

Brain-specific angiogenesis inhibitor 1 protein-coding gene in the species Homo sapiens

Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded by the BAI1 gene. It is a member of the adhesion-GPCR family of receptors.

WASF1

Wiskott–Aldrich syndrome protein family member 1, also known as WASP-family verprolin homologous protein 1 (WAVE1), is a protein that in humans is encoded by the WASF1 gene.

BAIAP2

Brain-specific angiogenesis inhibitor 1-associated protein 2 is a protein that in humans is encoded by the BAIAP2 gene.

BMX (gene)

Cytoplasmic tyrosine-protein kinase BMX is an enzyme that in humans is encoded by the BMX gene.

MTSS1 protein-coding gene in the species Homo sapiens

Metastasis suppressor protein 1 is a protein that in humans is encoded by the MTSS1 gene. True to its name, it codes for a metastasis suppressor.

BAIAP2L1 protein-coding gene in the species Homo sapiens

Brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 is a protein that in humans is encoded by the BAIAP2L1 gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

Non-receptor tyrosine kinases (nRTKs) are cytosolic enzymes that are responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

References

  1. 1 2 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.
  3. 1 2 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.
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