Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function

TY - JOUR

T1 - Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function

AU - Holm, Rikke

AU - Toustrup-Jensen, Mads Schak

AU - Einholm, Anja P.

AU - Schack, Vivien

AU - Andersen, Jens Peter

AU - Vilsen, Bente

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Na +,K +-ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na +,K +-ATPase exists as four isoforms (α1–α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na +,K +-ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na +,K +-ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na + and K + binding. In several cases the compromised function can be traced to disturbance of the Na + specific binding site III. Recently, a secondary mutation was found to rescue the defective Na + binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect.

AB - Na +,K +-ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na +,K +-ATPase exists as four isoforms (α1–α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na +,K +-ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na +,K +-ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na + and K + binding. In several cases the compromised function can be traced to disturbance of the Na + specific binding site III. Recently, a secondary mutation was found to rescue the defective Na + binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect.

KW - Alternating hemiplegia of childhood (AHC)

KW - Na ,K -pump

KW - Na site

KW - Protein structure

KW - Rapid-onset dystonia parkinsonism (RDP)

KW - Second-site mutation

UR - http://www.scopus.com/inward/record.url?scp=84987622640&partnerID=8YFLogxK

U2 - 10.1016/j.bbabio.2016.08.009

DO - 10.1016/j.bbabio.2016.08.009

M3 - Review

C2 - 27577505

SN - 0005-2728

VL - 1857

SP - 1807

EP - 1828

JO - B B A - Bioenergetics

JF - B B A - Bioenergetics

IS - 11

ER -