PR65, the HEAT-​repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis

Citation:

Grinthal A, Adamovic I, Weiner B, Karplus M, Kleckner N. PR65, the HEAT-​repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107 (6) :2467-2472.

Abstract:

PR65 is the two-​layered (α-​α solenoid) HEAT-​repeat scaffold of protein phosphatase PP2A. Mol. dynamics (MD) simulations predict that at forces expected in living systems, PR65 undergoes (visco-​)​elastic deformations in response to pulling​/pushing on its ends. At lower forces, smooth global flexural and torsional changes occur via even redistribution of stress along the hydrophobic core of the mol. At intermediate forces, helix-​helix sepn. along one layer ("fracturing") leads to global relaxation plus loss of contact in the other layer to unstack the affected units. Fracture sites are detd. by unusual sequences in contiguous interhelix turns. Normal mode anal. of the heterotrimeric PP2A enzyme reveals that its ambient conformational fluctuations are dominated by elastic deformations of PR65, which introduce a mech. linkage between the sep. bound regulatory and catalytic subunits. PR65-​dominated fluctuations of PP2A have the effect of opening and closing the enzyme's substrate binding​/catalysis interface, as well as altering the positions of certain catalytic residues. These results suggest that substrate binding​/catalysis are sensitive to mech. force. Force could be imposed from the outside (e.g., in PP2A's response to spindle tension) or arise spontaneously (e.g., in PP2A's interaction with unstructured proteins such as Tau, a microtubule-​assocd. Alzheimer's-​implicated protein)​. The present example supports the view that conformation and function of protein complexes can be modulated by mech. energy inputs, as well as by chem. energy inputs from ligand binding. Given that helical-​repeat proteins are involved in many cellular processes, the findings also encourage the view that mech. forces may be of widespread importance.