Biochemical Basis of Skin Disease Mal de Meleda: SLURP-1 Mutants Differently Affect Keratinocyte Proliferation and Apoptosis.

Abstract

Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with α7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a β-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, including those involved in Mal de Meleda pathogenesis. All mutants except R71H, R71P, T52A, R96P, and L98P were produced in the folded form. SLURP-1 reduces the growth of Het-1A keratinocytes; thus, we studied the influence of the mutations on its antiproliferative activity. Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity. Alanine substitutions of R96 and L98 residues located in the protein head resulted in the appearance of additional pro-apoptotic activity. Our results agree with the diversity of Mal de Meleda phenotypes. Using obtained functional data, the SLURP-1/α7 type nicotinic acetylcholine receptor complex was modeled in silico. Our study provides functional and structural information about the role of the SLURP-1 mutations in Mal de Meleda pathogenesis and predicts SLURP-1 variants, which could drive the disease.

• Authors: Mikhail A Shulepko, Maxim L Bychkov, Zakhar O Shenkarev, Dmitrii S Kulbatskii, Alexey M Makhonin, Alexander S Paramonov, Anton O Chugunov, Mikhail P Kirpichnikov, Ekaterina N Lyukmanova
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 9 Pg. 2229-2237 (09 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 33741389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Ly
• SLURP1 protein, human
• alpha7 Nicotinic Acetylcholine Receptor
• Urokinase-Type Plasminogen Activator

Topics

• Antigens, Ly (genetics, metabolism)
• Apoptosis
• Cell Line
• Cell Proliferation
• Disease Progression
• Humans
• Keratinocytes (metabolism, pathology)
• Keratoderma, Palmoplantar (genetics, metabolism, pathology)
• Mutagenesis, Site-Directed
• Mutation (genetics)
• Phenotype
• Protein Binding
• Protein Conformation
• Structure-Activity Relationship
• Urokinase-Type Plasminogen Activator (genetics, metabolism)
• alpha7 Nicotinic Acetylcholine Receptor (metabolism)