Összes szerző


Wacha András

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Závodszky Péter
Ligand-induced conformational rearrangements regulate the switch between functions of ROCK2

Aug 27 - kedd

17:00 – 19:00

I. Poszterszekció

P17

Ligand-induced conformational rearrangements regulate the switch between functions of ROCK2 

István Hajdú1, András Szilágyi1, Barbara Végh1, András Wacha2 Éva Gráczer1, Dániel Györffy1, Márk Somogyi1, Péter Závodszky1

1Institute of Enzymology, RCNS, HAS, Budapest,

2Institute of Materials and Environmental Chemistry. RCNS, HAS, Budapest

Rho-associated protein kinase 2 (ROCK2) is a membrane-anchored, long, flexible, multidomain, multifunctional protein. Its functions can be placed into two categories: membrane-proximal and membrane-distal ones. A recent study concluded that membrane–distal functions, e.g. regulatory myosin light chain (RMLC) phosphorylation requires a fully extended conformation, and this conclusion was supported by electron microscopy. The present solution small angle X-ray scattering (SAXS) study revealed that ROCK2 population is a dynamic mixture of folded and partially extended conformers. We have shown that the predicted, auto-inhibited, folded conformation of ROCK2 exists in solution, and is stabilized by weak non-covalent interactions between the N- and C-termini. Binding of RhoA to the coiled-coil domain shifts the equilibrium towards the partially extended state. The binding of natural protein substrates (e.g. LIMK1) to the kinase domain breaks up the interaction between the N-terminal kinase and C-terminal regulatory domains, but smaller substrate analogues do not. The present studies reflect the dynamic behaviour of this long, dimeric molecule in solution, and our structural model provides a mechanistic explanation for a set of membrane-proximal functions, while allowing for the existence of an extended conformation in the case of membrane-distal functions.