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J Chem Theory Comput. 2018 Feb 13;14(2):1033-1044. doi: 10.1021/acs.jctc.7b00766. Epub 2018 Jan 26.

The Structural Asymmetry of Mitochondrial Hsp90 (Trap1) Determines Fine Tuning of Functional Dynamics.

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IRCCS Multimedica , via Fantoli 16/15, 20138 Milano, Italy.
Howard Hughes Medical Institute and Department of Biochemistry & Biophysics, University of California , 600 16th Street, San Francisco, California 94158, United States.
Istituto di Chimica del Riconoscimento Molecolare , CNR Via Mario Bianco 9, 20131 Milano, Italy.
Dipartimento di Chimica, Università di Pavia , V.le Taramelli 12, 27100 Pavia, Italy.


The Hsp90 family of molecular chaperones oversees the folding of a wide range of client proteins. Hsp90 is a homodimer, whose conformational states and functions are regulated by ATP-binding and hydrolysis. The crystal structure of mitochondrial Hsp90 (Trap1) showed that one of the two protomers in the active state is buckled, resulting in an asymmetric conformation. The asymmetry between the two protomers corresponds to the broadly conserved region responsible for client binding. Moreover, asymmetry determines differential hydrolysis for each protomer, with the buckled conformation favoring ATP processing. Experimental results show that after the first hydrolysis the dimer flips to a different asymmetric state while remaining in a closed conformation for the second hydrolysis. In this model, asymmetry plays a key role in the mechanism that drives chaperone function. Herein, we investigate the nucleotide-dependent internal dynamics of Trap1 with computational approaches. Our results shed light on the relationship between the nucleotide state in the N-terminal domain and the asymmetric modulation of the dynamic and structural properties of the client-binding region in the Middle domain. According to our analysis, this is the region that undergoes the most intense dynamic modulation upon nucleotide exchange. This result provides molecular insights into the roles of structural asymmetry in the regulation of Trap1 and suggests that this substructure is a promising target to modulate the functionally oriented aspects of Trap1 dynamics, therefore opening fresh opportunities for the design of selective therapeutics for Trap1-dependent diseases.

[Indexed for MEDLINE]

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