Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification

Scott Pegan; Christine Arrabit; Wei Zhou; Witek Kwiatkowski; Anthony Collins; Paul A. Slesinger; Senyon Choe

doi:10.1038/nn1411

Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification

Scott Pegan
, Christine Arrabit
, Wei Zhou
, Witek Kwiatkowski
, Anthony Collins
, Paul A. Slesinger
, Senyon Choe

Research output: Contribution to journal › Article › peer-review

269 Scopus citations

Abstract

N- and C-terminal cytoplasmic domains of inwardly rectifying K (Kir) channels control the ion-permeation pathway through diverse interactions with small molecules and protein ligands in the cytoplasm. Two new crystal structures of the cytoplasmic domains of Kir2.1 (Kir2.1_L) and the G protein-sensitive Kir3.1 (Kir3.1_S) channels in the absence of PIP₂ show the cytoplasmic ion-permeation pathways occluded by four cytoplasmic loops that form a girdle around the central pore (G-loop). Significant flexibility of the pore-facing G-loop of Kir2.1_L and Kir3.1_S suggests a possible role as a diffusion barrier between cytoplasmic and transmembrane pores. Consistent with this, mutations of the G-loop disrupted gating or inward rectification. Structural comparison shows a di-aspartate cluster on the distal end of the cytoplasmic pore of Kir2.1 _L that is important for modulating inward rectification. Taken together, these results suggest the cytoplasmic domains of Kir channels undergo structural changes to modulate gating and inward rectification.

Original language	English
Pages (from-to)	279-287
Number of pages	9
Journal	Nature Neuroscience
Volume	8
Issue number	3
DOIs	https://doi.org/10.1038/nn1411
State	Published - Mar 2005
Externally published	Yes

Access to Document

10.1038/nn1411

Cite this

@article{fec158782a0540b1856c03f3e3c26cc2,

title = "Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification",

abstract = "N- and C-terminal cytoplasmic domains of inwardly rectifying K (Kir) channels control the ion-permeation pathway through diverse interactions with small molecules and protein ligands in the cytoplasm. Two new crystal structures of the cytoplasmic domains of Kir2.1 (Kir2.1L) and the G protein-sensitive Kir3.1 (Kir3.1S) channels in the absence of PIP2 show the cytoplasmic ion-permeation pathways occluded by four cytoplasmic loops that form a girdle around the central pore (G-loop). Significant flexibility of the pore-facing G-loop of Kir2.1L and Kir3.1S suggests a possible role as a diffusion barrier between cytoplasmic and transmembrane pores. Consistent with this, mutations of the G-loop disrupted gating or inward rectification. Structural comparison shows a di-aspartate cluster on the distal end of the cytoplasmic pore of Kir2.1 L that is important for modulating inward rectification. Taken together, these results suggest the cytoplasmic domains of Kir channels undergo structural changes to modulate gating and inward rectification.",

author = "Scott Pegan and Christine Arrabit and Wei Zhou and Witek Kwiatkowski and Anthony Collins and Slesinger, \{Paul A.\} and Senyon Choe",

note = "Funding Information: We thank D. Clapham, M. Lazdunski and S. Hebert for GIRK4, GIRK2 and ROMK1 cDNAs, respectively. We also thank D. Kaiser for analytical ultracentrifugation, C. Park for mass spectroscopy, and the staff at ALS and SSRL for X-ray data collection. This work was supported by grants from the National Institutes of Health (P.A.S \& S.C.) and the McKnight Endowment for Neuroscience (P.A.S). S.C. acknowledges the support from the American Heart Association.",

year = "2005",

month = mar,

doi = "10.1038/nn1411",

language = "English",

volume = "8",

pages = "279--287",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

number = "3",

}

TY - JOUR

T1 - Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification

AU - Pegan, Scott

AU - Arrabit, Christine

AU - Zhou, Wei

AU - Kwiatkowski, Witek

AU - Collins, Anthony

AU - Slesinger, Paul A.

AU - Choe, Senyon

N1 - Funding Information: We thank D. Clapham, M. Lazdunski and S. Hebert for GIRK4, GIRK2 and ROMK1 cDNAs, respectively. We also thank D. Kaiser for analytical ultracentrifugation, C. Park for mass spectroscopy, and the staff at ALS and SSRL for X-ray data collection. This work was supported by grants from the National Institutes of Health (P.A.S & S.C.) and the McKnight Endowment for Neuroscience (P.A.S). S.C. acknowledges the support from the American Heart Association.

PY - 2005/3

Y1 - 2005/3

N2 - N- and C-terminal cytoplasmic domains of inwardly rectifying K (Kir) channels control the ion-permeation pathway through diverse interactions with small molecules and protein ligands in the cytoplasm. Two new crystal structures of the cytoplasmic domains of Kir2.1 (Kir2.1L) and the G protein-sensitive Kir3.1 (Kir3.1S) channels in the absence of PIP2 show the cytoplasmic ion-permeation pathways occluded by four cytoplasmic loops that form a girdle around the central pore (G-loop). Significant flexibility of the pore-facing G-loop of Kir2.1L and Kir3.1S suggests a possible role as a diffusion barrier between cytoplasmic and transmembrane pores. Consistent with this, mutations of the G-loop disrupted gating or inward rectification. Structural comparison shows a di-aspartate cluster on the distal end of the cytoplasmic pore of Kir2.1 L that is important for modulating inward rectification. Taken together, these results suggest the cytoplasmic domains of Kir channels undergo structural changes to modulate gating and inward rectification.

AB - N- and C-terminal cytoplasmic domains of inwardly rectifying K (Kir) channels control the ion-permeation pathway through diverse interactions with small molecules and protein ligands in the cytoplasm. Two new crystal structures of the cytoplasmic domains of Kir2.1 (Kir2.1L) and the G protein-sensitive Kir3.1 (Kir3.1S) channels in the absence of PIP2 show the cytoplasmic ion-permeation pathways occluded by four cytoplasmic loops that form a girdle around the central pore (G-loop). Significant flexibility of the pore-facing G-loop of Kir2.1L and Kir3.1S suggests a possible role as a diffusion barrier between cytoplasmic and transmembrane pores. Consistent with this, mutations of the G-loop disrupted gating or inward rectification. Structural comparison shows a di-aspartate cluster on the distal end of the cytoplasmic pore of Kir2.1 L that is important for modulating inward rectification. Taken together, these results suggest the cytoplasmic domains of Kir channels undergo structural changes to modulate gating and inward rectification.

UR - https://www.scopus.com/pages/publications/14544298750

U2 - 10.1038/nn1411

DO - 10.1038/nn1411

M3 - Article

C2 - 15723059

AN - SCOPUS:14544298750

SN - 1097-6256

VL - 8

SP - 279

EP - 287

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 3

ER -

Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification

Abstract

Access to Document

Fingerprint

Cite this