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

Abstract

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.

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

“…56 The A domain contains a Thr-Gly-Glu -Ser motif that bonds, through the glutamate residue, the water molecule needed for aspartyl-phosphate hydrolysis in the catalytic site. 57 The transmembrane region is composed of 10 transmembrane helices (TM 1-10 ), of which helices TM 4-6 contain the cation binding sites and TM 8 contributes to the biding of the third Na + ion. 57,58 To allow ions exchange, during the reaction cycle the protein undergoes critical conformational changes, reversing the accessibility and specificity of the cation binding sites.…”

“…57 The transmembrane region is composed of 10 transmembrane helices (TM 1-10 ), of which helices TM 4-6 contain the cation binding sites and TM 8 contributes to the biding of the third Na + ion. 57,58 To allow ions exchange, during the reaction cycle the protein undergoes critical conformational changes, reversing the accessibility and specificity of the cation binding sites. 59 In the so-called E 1 state, the α subunit is accessible from the cytoplasmic side and is Na + -selective.…”

“…20 With regard to the affected functional domain, most AHC-causing variants affect the ions binding sites or the transmembrane segments that harbor the binding residues ( Figure 2). 57 A smaller group of mutations is found in transmembrane helices other than the ion binding segments. Furthermore, several mutations affect the cytoplasmic extensions of the transmembrane helices TM [3][4][5] , that connect these helices with the cytoplasmic A-, N-and P-domains (the so-called "stalk" mutations).…”

“…Furthermore, several mutations affect the cytoplasmic extensions of the transmembrane helices TM [3][4][5] , that connect these helices with the cytoplasmic A-, N-and P-domains (the so-called "stalk" mutations). 57 This latter cytoplasmic domain has been found to harbor several AHC-causing variants, while a small group of pathogenic variants have been found to affect the extracellular loop between TM 7 and TM 8 .…”

“…As a result, a vast proportion of AHC-causing variants are expected to affect the ion binding and transport, while another consistent group of mutations is expected to affect enzyme phosphorylation. 57 For some of the ion-binding sites mutations (Asp801Asn, Asp923Asn, Ser137Tyr, Phe780Leu, Ile810Asn), experimental evidence of defective Na + binding has been provided, [69][70][71] while for other variants impaired Na + binding has been shown with mutations affecting the corresponding residue in the α 1 paralog. 57 Of note, few mutations have been reported in the transmembrane helices far from the ionbinding sites (such as TM 1-2 and TM 9-10 ).…”