Conformational Motions Regulate Phosphoryl Transfer in Related Protein Tyrosine Phosphatases

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Science  23 Aug 2013:
Vol. 341, Issue 6148, pp. 899-903
DOI: 10.1126/science.1241735

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Closing the Loop

Many studies have shown that protein dynamics are important to enzyme function. For example, enzyme protein movements have been shown to optimize the active site, enable binding of substrate and cofactor, and facilitate product release. Whittier et al. (p. 899) now show that in two tyrosine phosphatases, the rate of cleavage is coupled to motion of a loop. The two phosphatases have different catalytic rates; however, in both, a loop containing a catalytic residue switches between an inactive open and a catalytically competent closed state. The rates of closure are equivalent to the cleavage rates, suggesting that the leaving group tyrosine is protonated simultaneously with loop closure. Thus, tuning of the loop motion plays a regulatory role in the catalytic cycle.


Many studies have implicated a role for conformational motions during the catalytic cycle, acting to optimize the binding pocket or facilitate product release, but a more intimate role in the chemical reaction has not been described. We address this by monitoring active-site loop motion in two protein tyrosine phosphatases (PTPs) using nuclear magnetic resonance spectroscopy. The PTPs, YopH and PTP1B, have very different catalytic rates; however, we find in both that the active-site loop closes to its catalytically competent position at rates that mirror the phosphotyrosine cleavage kinetics. This loop contains the catalytic acid, suggesting that loop closure occurs concomitantly with the protonation of the leaving group tyrosine and explains the different kinetics of two otherwise chemically and mechanistically indistinguishable enzymes.

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