The Transition State of Coupled Folding and Binding for a Flexible beta-Finger

Karlsson, O. Andreas (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi

Chi, Celestine N., 1978- (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,ETH, Lab Phys Chem, Zurich, Switzerland,Chi Celestine

Engström, Åke (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi

Jemth, Per (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi

(creator_code:org_t)

Elsevier BV, 2012
2012
English.
In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 417:3, s. 253-261

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; show less...

Abstract Subject headings

Flexible and fully disordered protein regions that fold upon binding mediate numerous protein protein interactions. However, little is known about their mechanism of interaction. One such coupled folding and binding occurs when a flexible region of neuronal nitric oxide synthase adopts a beta-finger structure upon binding to its protein ligand, a PDZ [PSD-95 (postsynaptic density protein-95)/Discs large/ZO-1] domain from PSD-95. We have analyzed this binding reaction by protein engineering combined with kinetic experiments. Mutational destabilization of the beta-finger changed mainly the dissociation rate constant of the proteins and, to a lesser extent, the association rate constant. Thus, mutation affected late events in the coupled folding and binding reaction. Our results therefore suggest that the native binding interactions of the beta-finger are not present in the rate-limiting transition state for binding but form on the downhill side in a cooperative manner. However, by mutation, we could destabilize the beta-finger further and change the rate-limiting step such that an initial conformational change becomes rate limiting. This switch in rate-limiting step shows that multistep binding mechanisms are likely to be found among flexible and intrinsically disordered regions of proteins.

By the author/editor: Karlsson, O. And ...; Chi, Celestine N ...; Engström, Åke; Jemth, Per

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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