KCa3.1, also known as SK4 or IK1, is a member of a family of small- to intermediate-conductance potassium channels in humans (KCa2.1?2.3, KCa3.1). KCa3.1 plays a crucial role in T-cell activation by effluxing potassium to maintain a negative membrane potential that allows for additional calcium influx. KCa3.1 is a potential therapeutic target for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and for organ transplant rejection. KCa3.1 (and KCa2.1?2.3) is homotetrameric and activated through calcium binding to calmodulin (CaM), which is constitutively associated with a cytoplasmic region of the channels (CaM binding domain, CaMBD). A novel feature of KCa3.1 activation is the additional requirement of phosphorylation of a specific histidine residue (His358), just downstream of the CaMBD, by NDPK-B (nucleoside diphosphate kinase-B). Although histidine phosphorylation is well characterized in two-component signaling systems in prokaryotes, the functional consequences of histidine phosphorylation in eukaryotes are just beginning to be understood. Recently, we showed that histidine phosphorylation of KCa3.1 is necessary to relieve copper inhibition of the channel. In this application, cryo-EM studies are proposed to elucidate the molecular mechanisms by which KCa3.1 is regulated by calcium and histidine phosphorylation.

Public Health Relevance

The potassium channel KCa3.1 plays a crucial role in immunity by effluxing potassium ions from T cells, which allows the influx of additional calcium ions to activate T cells. This proposal seeks to characterize by cryo- electron microscopy the three-dimensional structures of KCa3.1 in its closed and open states. KCa3.1 is a potential therapeutic target for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and for organ transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI144354-01A1
Application #
9979098
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Rothermel, Annette L
Project Start
2020-01-31
Project End
2021-12-31
Budget Start
2020-01-31
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016