期刊
BIOCHEMISTRY
卷 47, 期 47, 页码 12346-12356出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi801308y
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资金
- NCRR NIH HHS [S10 RR017269, S10 RR020923, 1S10RR020923, S10-RR017269] Funding Source: Medline
- NIMH NIH HHS [P50 MH074866] Funding Source: Medline
- NINDS NIH HHS [R01 NS056128, R01 NS056128-02, R01NS056128] Funding Source: Medline
Protein phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine protein phosphatase that is regulated by more than 100 known inhibitor and targeting proteins. It is currently unclear how protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demonstrate that two PP1 inhibitors, I-2 and DARPP-32, belong to the class of intrinsically unstructured proteins (IUPs). We show that both inhibitors have distinct preferences for transient local and long-range structure. These preferences are likely their structural signature for their interaction with PP1. Furthermore, we show that upon phosphorylation of Thr(34) in DARPP-32, which turns DARPP-32 into a potent inhibitor of PP1, neither local nor long-range structure of DARPP-32 is altered. Therefore, our data suggest a role for these transient three-dimensional topologies in binding mechanisms that enable extensive contacts with PP1's invariant surfaces. Together, these interactions enable potent and selective inhibition of PP1.
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