PDBsum entry 4u84

Isomerase

PDB id: 4u84

Contents

Protein chain

145 a.a.

Ligands

15P

Waters ×101

PDB id:

4u84

Name:

Isomerase

Title:

Human pin1 with s-hydroxyl-cysteine 113

Structure:

Peptidyl-prolyl cis-trans isomerase nima-interacting 1. Chain: a. Synonym: peptidyl-prolyl cis-trans isomerase pin1,ppiase pin1, rotamase pin1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pin1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.78Å R-factor: 0.197 R-free: 0.224

Authors:

W.Li,Y.Zhang

Key ref:

C.H.Chen et al. (2015). Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis, 76, 13-23. PubMed id: 25576397 DOI: 10.1016/j.nbd.2014.12.027

Date:

01-Aug-14 Release date: 08-Apr-15

Protein chain

Q13526  (PIN1_HUMAN) -  Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 from Homo sapiens

Seq: 163 a.a.

Struc: 145 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.nbd.2014.12.027

Neurobiol Dis 76:13-23 (2015)

PubMed id: 25576397

Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease.

C.H.Chen, W.Li, R.Sultana, M.H.You, A.Kondo, K.Shahpasand, B.M.Kim, M.L.Luo, M.Nechama, Y.M.Lin, Y.Yao, T.H.Lee, X.Z.Zhou, A.M.Swomley, D.Allan Butterfield, Y.Zhang, K.P.Lu.

ABSTRACT

The unique proline isomerase Pin1 is pivotal for protecting against age-dependent neurodegeneration in Alzheimer's disease (AD), with its inhibition providing a molecular link between tangle and plaque pathologies. Pin1 is oxidatively modified in human AD brains, but little is known about its regulatory mechanisms and pathological significance of such Pin1 modification. In this paper, our determination of crystal structures of oxidized Pin1 reveals a series of Pin1 oxidative modifications on Cys113 in a sequential fashion. Cys113 oxidization is further confirmed by generating antibodies specifically recognizing oxidized Cys113 of Pin1. Furthermore, Pin1 oxidation on Cys113 inactivates its catalytic activity in vitro, and Ala point substitution of Cys113 inactivates the ability of Pin1 to isomerize tau as well as to promote protein turnover of tau and APP. Moreover, redox regulation affects Pin1 subcellular localization and Pin1-mediated neuronal survival in response to hypoxia treatment. Importantly, Cys113-oxidized Pin1 is significantly increased in human AD brain comparing to age-matched controls. These results not only identify a novel Pin1 oxidation site to be the critical catalytic residue Cys113, but also provide a novel oxidative regulation mechanism for inhibiting Pin1 activity in AD. These results suggest that preventing Pin1 oxidization might help to reduce the risk of AD.