Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia

Rachit M. Shah, Kimberly M Maize, Harrison T West, Alexander M. Strom, Barry C Finzel, Carston R Wagner

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.

Original languageEnglish (US)
Pages (from-to)2709-2721
Number of pages13
JournalJournal of Molecular Biology
Volume430
Issue number17
DOIs
StatePublished - Aug 17 2018

Fingerprint

Isaacs Syndrome
Mutation
Enzymes
Adenosine Monophosphate
Histidine
Neurodegenerative Diseases
Catalytic Domain
human HINT1 protein
human NUBP1 protein
histidine-binding protein

Keywords

  • HINT1
  • neuromyotonia
  • neuropathy
  • phosphoramidase

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia. / Shah, Rachit M.; Maize, Kimberly M; West, Harrison T; Strom, Alexander M.; Finzel, Barry C; Wagner, Carston R.

In: Journal of Molecular Biology, Vol. 430, No. 17, 17.08.2018, p. 2709-2721.

Research output: Contribution to journalArticle

@article{17caa7553a7749bcbbfa2cc94b1f1ee1,
title = "Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia",
abstract = "Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.",
keywords = "HINT1, neuromyotonia, neuropathy, phosphoramidase",
author = "Shah, {Rachit M.} and Maize, {Kimberly M} and West, {Harrison T} and Strom, {Alexander M.} and Finzel, {Barry C} and Wagner, {Carston R}",
year = "2018",
month = "8",
day = "17",
doi = "10.1016/j.jmb.2018.05.028",
language = "English (US)",
volume = "430",
pages = "2709--2721",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "17",

}

TY - JOUR

T1 - Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia

AU - Shah, Rachit M.

AU - Maize, Kimberly M

AU - West, Harrison T

AU - Strom, Alexander M.

AU - Finzel, Barry C

AU - Wagner, Carston R

PY - 2018/8/17

Y1 - 2018/8/17

N2 - Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.

AB - Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.

KW - HINT1

KW - neuromyotonia

KW - neuropathy

KW - phosphoramidase

UR - http://www.scopus.com/inward/record.url?scp=85047632119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047632119&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2018.05.028

DO - 10.1016/j.jmb.2018.05.028

M3 - Article

C2 - 29787766

AN - SCOPUS:85047632119

VL - 430

SP - 2709

EP - 2721

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 17

ER -