BN-SEMINAR

Time: Friday 12:00 - 13:30 (lunch included)

Location: Room F105

Local speaker: Gregory Schneider (Cees Dekker's lab)

Invited speaker:

Daniel Abankwa, from the Centre for Biotechnolgy in Turku (Finland).

Abstract:

The Ras superfamily of GTPases contains more than 150 similar proteins, with 39 alone in the Ras family. Understanding which structural elements encode specific functioning of Ras proteins is a fundamental biological problem. Insight into the associated molecular mechanisms will also provide new pharmacological targets to inhibit specific Ras proteins. We recently reported a novel switch III and associated orientation mechanism of Ras, where the G- domain activation state dependently reorientates onto the membrane. This is recognized by the Ras effectors C-Raf, phosphoinositide-3-kinase-α and the scaffolding protein galectin-1. Thus membrane orientation is coupled to Rassignalling and MAPK-dependent differentiation of PC12 cells. Moreover, membrane orientation is critically tuned by the switched elements, helix α4 and the HVR, which operate the G-domain like a balance (balance model). GTPase orientation then combines with its lateral segregation into distinct nanoclusters, thus generating Ras isoform specificity by selective effector interactions. Given the basic conservation of the G domain, we propose that this novel mechanism also operates in other small GTPases. Finally, we show, how nanoclustering can be exploited to build novel assays for highthroughput screening for specific inhibitors of GTPase-signalling.