PDBsum entry 2mng

Transport protein

PDB id: 2mng

Contents

Protein chain

131 a.a.

PDB id:

2mng

Name:

Transport protein

Title:

Apo structure of human hcn4 cnbd solved by nmr

Structure:

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4. Chain: a. Fragment: cyclic amp binding domain (unp residues 579-707). Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hcn4. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

10 models

Authors:

M.Akimoto,Z.Zhang,S.Boulton,R.Selvaratnam,B.Vanschouwen,M.Gloyd, E.A.Accili,O.F.Lange,G.Melacini

Key ref:

M.Akimoto et al. (2014). A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. J Biol Chem, 289, 22205-22220. PubMed id: 24878962 DOI: 10.1074/jbc.M114.572164

Date:

03-Apr-14 Release date: 04-Jun-14

Protein chain

Q9Y3Q4  (HCN4_HUMAN) -  Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 from Homo sapiens

Seq: 1203 a.a.

Struc: 131 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1074/jbc.M114.572164

J Biol Chem 289:22205-22220 (2014)

PubMed id: 24878962

A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP.

M.Akimoto, Z.Zhang, S.Boulton, R.Selvaratnam, B.VanSchouwen, M.Gloyd, E.A.Accili, O.F.Lange, G.Melacini.

ABSTRACT

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels control neuronal and cardiac electrical rhythmicity. There are four homologous isoforms (HCN1-4) sharing a common multidomain architecture that includes an N-terminal transmembrane tetrameric ion channel followed by a cytoplasmic "C-linker," which connects a more distal cAMP-binding domain (CBD) to the inner pore. Channel opening is primarily stimulated by transmembrane elements that sense membrane hyperpolarization, although cAMP reduces the voltage required for HCN activation by promoting tetramerization of the intracellular C-linker, which in turn relieves auto-inhibition of the inner pore gate. Although binding of cAMP has been proposed to relieve auto-inhibition by affecting the structure of the C-linker and CBD, the nature and extent of these cAMP-dependent changes remain limitedly explored. Here, we used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo-CBD of HCN4. Our data indicate that the CBD exists in a dynamic two-state equilibrium, whose position as gauged by NMR chemical shifts correlates with the V½ voltage measured through electrophysiology. In the absence of cAMP, the most populated CBD state leads to steric clashes with the activated or "tetrameric" C-linker, which becomes energetically unfavored. The steric clashes of the apo tetramer are eliminated either by cAMP binding, which selects for a CBD state devoid of steric clashes with the tetrameric C-linker and facilitates channel opening, or by a transition of apo-HCN to monomers or dimer of dimers, in which the C-linker becomes less structured, and channel opening is not facilitated.