Abstract
The 14kDa histidine triad nucleotide-binding protein 1 (HINT1) is critical to maintain the normal function of motor neurons. Thus, a series of human HINT1 mutants cause autosomal recessive axonal neuropathy with neuromyotonia. HINT1 establishes a series of regulatory interactions with signaling proteins, some of which are enriched in motor neurons, such as the type 1 sigma receptor or intracellular domain (ICD) of transmembrane teneurin 1, both of which are also implicated in motor disturbances. In a previous study, we reported the capacity of HINT1 to remove the small ubiquitin-like modifier (SUMO) from a series of substrates and the influence of HINT1 mutants on this activity. We now report how human HINT1 mutations affect the interaction of HINT1 with the regulator of its SUMOylase activity, calcium-activated calmodulin, and its substrate SUMO. Moreover, HINT1 mutants exhibited anomalous interactions with G protein coupled receptors, such as the mu-opioid, and with glutamate N-methyl-D-aspartate receptors as well. Additionally, these HINT1 mutants showed impaired associations with transcriptional regulators such as the regulator of G protein signaling Z2 protein and the cleaved N-terminal ICD of teneurin 1. Thus, the altered enzymatic activity of human HINT1 mutants and their anomalous interactions with partner proteins may disrupt signaling pathways essential to the normal function of human motor neurons.
Highlights
Histidine triad nucleotide-binding protein 1 (HINT1) is highly phylogenically conserved [1] and belongs to the histidine triad (HIT) family
histidine triad nucleotide-binding protein 1 (HINT1) establishes a series of regulatory interactions with signaling proteins, some of which are enriched in motor neurons, such as the type 1 sigma receptor or intracellular domain (ICD) of transmembrane teneurin 1, both of which are implicated in motor disturbances
The CaM-binding motif is located in the HINT1 N-terminal region (12–31 QPGGDTIFGKIIRKEIPAKI) [27], and in a β-sheet close to the C-terminus, a series of hydrophobic amino acids (110–116: HIHLHVL) form the typical composition of a small ubiquitin-like modifier (SUMO)-interacting motif (SIM) [28] (Fig. 1A)
Summary
Histidine triad nucleotide-binding protein 1 (HINT1) is highly phylogenically conserved [1] and belongs to the histidine triad (HIT) family This 14 kDa protein exhibits zinc- and calmodulin (CaM)-regulated protease activity to remove small-ubiquitin-like modifier (SUMO) from target proteins [2]. A rare form of hereditary peripheral neuropathy named autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) has convincingly being related to mutations in the HINT1 gene. These patients present muscle weakness, wasting and sensory loss, which starts in the distal parts of the limbs and slowly progresses in a length-dependent manner [3, 4]. This finding suggests that human HINT1 mutant proteins, by interacting with third-partner signaling proteins, cause the disease, and some of these interactions may play a relevant role in motor neuron function
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