6UUQ

Structure of Calcineurin bound to RCAN1

Summary for 6UUQ

• Entry DOI: 10.2210/pdb6uuq/pdb
• Descriptor: Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform, Calcipressin-1, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: ser/thr phosphatase, hydrolase, hydrolase-signaling protein complex, hydrolase/signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 41122.71

Authors

Sheftic, S.,Page, R.,Peti, W. (deposition date: 2019-10-31, release date: 2020-09-09, Last modification date: 2024-10-23)

Primary citation

Li, Y.,Sheftic, S.R.,Grigoriu, S.,Schwieters, C.D.,Page, R.,Peti, W.
The structure of the RCAN1:CN complex explains the inhibition of and substrate recruitment by calcineurin.
Sci Adv, 6:-, 2020

PubMed Abstract: Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the Ser/Thr phosphatase calcineurin (CN). It has been shown that excessive inhibition of CN is a critical factor for Down syndrome and Alzheimer's disease. Here, we determined RCAN1's mode of action. Using a combination of structural, biophysical, and biochemical studies, we show that RCAN1 inhibits CN via multiple routes: first, by blocking essential substrate recruitment sites and, second, by blocking the CN active site using two distinct mechanisms. We also show that phosphorylation either inhibits RCAN1-CN assembly or converts RCAN1 into a weak inhibitor, which can be reversed by CN via dephosphorylation. This highlights the interplay between posttranslational modifications in regulating CN activity. Last, this work advances our understanding of how active site inhibition of CN can be achieved in a highly specific manner. Together, these data provide the necessary road map for targeting multiple neurological disorders.

PubMed: 32936779
DOI: 10.1126/sciadv.aba3681

Experimental method

X-RAY DIFFRACTION (1.849 Å)