It's a wrap!

The Wiskott–Aldrich syndrome protein (WASP) and its homologue N-WASP promote actin polymerization in response to upstream signals, and their importance is highlighted by the Wiskott–Aldrich syndrome (WAS) — an immune disorder that is caused primarily by missense mutations in the Enabled/VASP homology 1 (EVH1) domain of WASP. Although the WASP/N-WASP EVH1 domain has been proposed to bind both phosphoinositides and peptides, these proposals have remained unconfirmed. However, work now published by Lim and colleagues in Cell has increased our understanding of both the binding interactions of the WASP/N-WASP EVH1 domain and the effects of WAS-causing mutations.

The authors began by showing that the N-WASP EVH1 domain and other EVH1 domains do not bind phosphatidylinositol-4,5-bisphosphate as was previously thought. They showed, however, that N-WASP EVH1 specifically binds to 25 residues of the WASP-interacting protein (WIP). When they determined the NMR structure of the N-WASP EVH1–WIP complex, they found that, although the overall structure of N-WASP EVH1 was the same as that for other EVH1 domains, N-WASP EVH1 recognizes peptides in a new way. WIP, which is more than double the size of other EVH1 ligands, wraps itself around the EVH1 domain “...like a piece of string around a spool...”, and contacts areas of the EVH1-domain surface that are well outside the canonical EVH1 peptide-binding site. This work has therefore identified a new (or hybrid) class of protein–protein interaction, and has also provided insights into how WAS-causing mutations affect the WASP/WIP interaction. REFERENCE Volkman, B. F. et al. Structure of the N-WASP EVH1 domain–WIP complex: insights into the molecular basis of Wiskott–Aldrich syndrome. Cell 111, 565–576 (2002)

The sensitive type

The inner membrane of Escherichia coli contains a 'mechanosensitive channel of small conductance' (MscS) that can transport ions (preferably anions) in response to cell-membrane depolarization and stretching. Although, there has recently been progress in our understanding of the mechanism of voltage-dependent channel gating, there had been no structural insights. Now, however, in Science, Rees and colleagues report the 3.9-Å-resolution crystal structure of 'open' MscS.

They found that MscS forms a homoheptamer, with a transmembrane (TM) region and a large carboxy-terminal cytoplasmic region (the amino terminus of MscS is periplasmic). Each subunit contains three TM helices (TM1–3), and it is the TM3 helices that form the pore. The pore is linked to a large chamber in the cytoplasmic region, and this chamber is linked to the cytoplasm through eight openings. The authors suggest that these openings act as molecular filters to check molecules before they enter the pore.

TM1 and TM2 flank the pore, although they are slightly displaced from it, and Rees and co-workers propose that these flanking helices, with their membrane-embedded arginines, mediate the tension and voltage sensitivities of MscS. Although MscS is probably structurally distinct from other ion channels, the importance of these results lies in the structural organization of MscS, which seems to be relevant to the gating mechanisms of other channels. REFERENCE Bass, R. B. et al. Crystal structure of Escherichia coli MscS, a voltage-modulated and mechanosensitive channel. Science 298, 1582–1587 (2002)