Molecular Mechanisms of Membrane Deformation by I-BAR Domain Proteins

Abstract

These data define I-BAR domain as a functional member of the BAR domain superfamily and unravel the mechanisms by which I-BAR domains deform membranes to induce filopodia in cells. Furthermore, our work reveals unexpected divergence in the mechanisms by which evolutionarily distinct groups of I-BAR domains interact with PI(4,5)P(2)-rich membranes.

MTSS1 is a metastasis driver in a subset of human melanomas

“…Physical interaction between MTSS1 and Rac has been documented earlier; to the best of our knowledge, however, RhoA-MTSS1 engagement has previously not been reported. While these data are supported by observations from other cell lines where ectopic expression of MTSS1 or its I-BAR domain results in reduction of stress fibers 35 , a hallmark phenotype for RhoA inactivation 62 , they do not exclude additional indirect Rac and RhoA regulation through MTSS1 by affecting the geometry or lipid distribution of the leading edge plasma membrane through its I-BAR domain 26 or by altering the structure of the actin cytoskeleton through its interactions with cortactin or Daam1 formin 63,64 . It is also interesting to note that in contrast to earlier reports about MTSS1 to activate Rac 37 , but consistent with Rac's dispensability for I-BAR-induced filopodia formation 34 , we observed a reduction of Rac activity in HMEL cells upon MTSS1 expression.…”

“…Two of these genes have an already proposed or documented role in melanoma cell biology with SHC1 acting on RAS signalling 22 and LAMP1 being implicated in melanoma metastasis 23 , thus supporting the potential biological significance of the applied selection approach. As we were particularly interested in the identification of drivers of the disease and, in contrast to SSR2-an endoplasmic reticulum translocon component 24 , MTSS1's property (MIM, KIAA0429) to regulate actin and plasma membrane dynamics via interaction with actin 25,26 provided a potential link to the phenotype in the invasion assay screen, we decided to study the contribution of MTSS1 to melanoma cell biology in more detail. The probe set 203037_s_at corresponding to MTSS1 showed an outlier profile in four out of 31 (13%) primary human melanoma samples (Fig.…”

“…MTSS1 senses and generates membrane curvature through its N-terminal I-BAR domain (inverse Bin/Amphiphysin/Rvs domain, also known as IRSp53/MIM homology domain or I-BAR/IMD) and interacts with actin monomers through its C-terminal WASP homology 2 (WH2) domain 26,34,35 . Furthermore, studies by the group of L. M. Machesky demonstrated that MTSS1 mediates activation of Rac via its I-BAR domain 36,37 .…”

Enterohemorrhagic Escherichia coli raises the I-BAR

“…Positively-charged amino acids thought to participate in membrane binding are concentrated at either ends of the dimer. The IRTKS and IRSp53 IMDs are homologous and biochemically similar (11). Each interacts with phosphatidylinositol 4,5-bisphosphate in the membrane and bends the membrane via electrostatic forces (11).…”

“…The IRTKS and IRSp53 IMDs are homologous and biochemically similar (11). Each interacts with phosphatidylinositol 4,5-bisphosphate in the membrane and bends the membrane via electrostatic forces (11). Expression of IMD from IRSp53 or IRTKS in cells produces filopodia-like protrusive structures of the plasma membrane, and interaction of these IMDs with phospholipidcontaining membrane vesicles in vitro induces the formation of membrane tubules (11,12).…”