7UIR

Cocrystal structure of human CaMKII-alpha (CAMK2A)kinase domain and Tiam1 in complex with ATP

Replaces:  6XF0

Summary for 7UIR

• Entry DOI: 10.2210/pdb7uir/pdb
• Related: 6X5G
• Descriptor: Calcium/calmodulin-dependent protein kinase type II subunit alpha, T-lymphoma invasion and metastasis-inducing protein 1, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: camkii, kinase, human, camk2a, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 66718.49

Authors

Ozden, C.,Stratton, M.M.,Garman, S.C. (deposition date: 2022-03-29, release date: 2022-04-06, Last modification date: 2023-10-18)

Primary citation

Ozden, C.,Sloutsky, R.,Mitsugi, T.,Santos, N.,Agnello, E.,Gaubitz, C.,Foster, J.,Lapinskas, E.,Esposito, E.A.,Saneyoshi, T.,Kelch, B.A.,Garman, S.C.,Hayashi, Y.,Stratton, M.M.
CaMKII binds both substrates and activators at the active site.
Cell Rep, 40:111064-111064, 2022

PubMed Abstract: Ca/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca/CaM, it sustains activity even after the Ca dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation.

PubMed: 35830796
DOI: 10.1016/j.celrep.2022.111064

Experimental method

X-RAY DIFFRACTION (3.1 Å)