TY - JOUR
T1 - Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent
AU - Ranganathan, Rama
AU - Lu, Kun Ping
AU - Hunter, Tony
AU - Noel, Joseph P.
N1 - Funding Information:
Correspondence regarding this paper should be addressed to J. P. N. We thank David Schultz and Charles Zuker for use of PPIase assay reagents; Hartmut Oschkinat for providing the YAP65 WW domain coordinates; Carl Hoeger for peptide synthesis; and Marianne Bowman, Eugene Lee, Matthew Harrington, and Michael Reese for technical assistance. We thank Courtney Starks, Alexandrine Bilwes, and the staff of the Stanford Synchrotron Radiation Laboratory for assistance at beamline 7-1. The work performed was supported by the NIH and DOE (SSRL) and in part by funds from the Lucille P. Markey Charitable Trust (J. P. N.) and USPHS grant CA54418 (J. P. N.). R. R. was a Burroughs-Wellcome Fund Fellow of the Life Sciences Research Foundation. K. P. L. was a Leukemia Society of America Fellow, and T. H. is an American Cancer Society Research Professor. Correspondence and requests for materials should be addressed to J. P. N. Until deposition in the Brookhaven Protein Data Bank, coordinates can be obtained from the following e-mail address: [email protected].
PY - 1997/6/13
Y1 - 1997/6/13
N2 - The human rotamase or peptidyl-prolyl cis-trans isomerase Pin1 is a conserved mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle. We report the 1.35 Å crystal structure of Pin1 complexed with an AlaPro dipeptide and the initial characterization of Pin1's functional properties. The crystallographic structure as well as pH titration studies and mutagenesis of an active site cysteine suggest a catalytic mechanism that includes general acid-base and covalent catalysis during peptide bond isomerization. Pin1 displays a preference for an acidic residue N-terminal to the isomerized proline bond due to interaction of this acidic side chain with a basic cluster. This raises the possibility of phosphorylation-mediated control of Pin1-substrate interactions in cell cycle regulation.
AB - The human rotamase or peptidyl-prolyl cis-trans isomerase Pin1 is a conserved mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle. We report the 1.35 Å crystal structure of Pin1 complexed with an AlaPro dipeptide and the initial characterization of Pin1's functional properties. The crystallographic structure as well as pH titration studies and mutagenesis of an active site cysteine suggest a catalytic mechanism that includes general acid-base and covalent catalysis during peptide bond isomerization. Pin1 displays a preference for an acidic residue N-terminal to the isomerized proline bond due to interaction of this acidic side chain with a basic cluster. This raises the possibility of phosphorylation-mediated control of Pin1-substrate interactions in cell cycle regulation.
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U2 - 10.1016/S0092-8674(00)80273-1
DO - 10.1016/S0092-8674(00)80273-1
M3 - Article
C2 - 9200606
AN - SCOPUS:0008233581
SN - 0092-8674
VL - 89
SP - 875
EP - 886
JO - Cell
JF - Cell
IS - 6
ER -