2RUC

Solution structure of the peptidyl prolyl cis-trans isomerase domain of human Pin1 with sulfate ion

Summary for 2RUC

• Entry DOI: 10.2210/pdb2ruc/pdb
• Related: 2RUD
• NMR Information: BMRB: 11559
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (1 entity in total)
• Functional Keywords: protein/cis-trans-isomerase, ppiase, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 1
• Total formula weight: 13121.73

Authors

Xu, N.,Tamari, Y.,Tochio, N.,Tate, S. (deposition date: 2014-03-25, release date: 2014-12-17, Last modification date: 2024-05-15)

Primary citation

Xu, N.,Tochio, N.,Wang, J.,Tamari, Y.,Uewaki, J.,Utsunomiya-Tate, N.,Igarashi, K.,Shiraki, T.,Kobayashi, N.,Tate, S.
The C113D mutation in human Pin1 causes allosteric structural changes in the phosphate binding pocket of the PPIase domain through the tug of war in the dual-histidine motif.
Biochemistry, 53:5568-5578, 2014

PubMed Abstract: Pin1 peptidyl-prolyl isomerase (PPIase) catalyzes specifically the pSer/pThr-Pro motif. The cis-trans isomerization mechanism has been studied by various approaches, including X-ray crystallography, site-directed mutagenesis, and the kinetic isotope effect on isomerization. However, a complete picture of the reaction mechanism remains elusive. On the basis of the X-ray structure of Pin1, residue C113 was proposed to play a nucleophile attacker to catalyze the isomerization. The controversial result that the C113D Pin1 mutant retains the activity, albeit at a reduced level, challenges the importance of C113 as a catalyst. To facilitate our understanding of the Pin1 isomerization process, we compared the structures and dynamics of the wild type with those of the C113D mutant Pin1 PPIase domains (residues 51-163). We found the C113D mutation disturbed the hydrogen bonds between the conserved histidine residues, H59 and H157 ("dual-histidine motif"); H59 imidazole forms a stable hydrogen bond to H157 in the wild type, whereas it has a strong hydrogen bond to D113 with weakened bonding to H157 in the C113D mutant. The C113D mutation unbalanced the hydrogen bonding tug of war for H59 between C113/D113 and H157 and destabilized the catalytic site structure, which eventually resulted in an altered conformation of the basic triad (K63, R68, and R69) that binds to the phosphate group in a substrate. The change in the basic triad structure could explain the severely weakened substrate binding ability of the C113D mutant. Overall, this work demonstrated that C113 plays a role in keeping the catalytic site in an active fold, which has never before been described.

PubMed: 25100325
DOI: 10.1021/bi5007817

Experimental method

SOLUTION NMR