Molecular basis of perinatal hypophosphatasia with tissue-nonspecific alkaline phosphatase bearing a conservative replacement of valine by alanine at position 406. Structural importance of the crown domain

The FEBS Journal
Natsuko NumaKimimitsu Oda

Abstract

Hypophosphatasia, a congenital metabolic disease related to the tissue-nonspecific alkaline phosphatase gene (TNSALP), is characterized by reduced serum alkaline phosphatase levels and defective mineralization of hard tissues. A replacement of valine with alanine at position 406, located in the crown domain of TNSALP, was reported in a perinatal form of hypophosphatasia. To understand the molecular defect of the TNSALP (V406A) molecule, we examined this missense mutant protein in transiently transfected COS-1 cells and in stable CHO-K1 Tet-On cells. Compared with the wild-type enzyme, the mutant protein showed a markedly reduced alkaline phosphatase activity. This was not the result of defective transport and resultant degradation of TNSALP (V406A) in the endoplasmic reticulum, as the majority of newly synthesized TNSALP (V406A) was conveyed to the Golgi apparatus and incorporated into a cold detergent insoluble fraction (raft) at a rate similar to that of the wild-type TNSALP. TNSALP (V406A) consisted of a dimer, as judged by sucrose gradient centrifugation, suggestive of its proper folding and correct assembly, although this mutant showed increased susceptibility to digestion by trypsin or proteinase K. When purified as a gly...Continue Reading

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Citations

Jan 9, 2010·Bioscience, Biotechnology, and Biochemistry·Hiroki TsurutaYasuo Aizono
Oct 1, 2009·Human Mutation·Tse Siang Kang, Raymond C Stevens
May 5, 2010·Journal of Molecular Biology·Andy WendeMartin Grininger
Jun 22, 2019·Expert Review of Proteomics·Gary B Smejkal, Srikanth Kakumanu
Oct 26, 2016·Protein Science : a Publication of the Protein Society·Jonathan ExtanceSusan J Crennell
Sep 14, 2017·Protein Science : a Publication of the Protein Society·Stuart McNicholasJon Agirre
Dec 1, 2012·Expert Review of Proteomics·Gary B Smejkal
Aug 11, 2019·Journal of Oral Biosciences·Keiichi KomaruKimimitsu Oda
Nov 4, 2008·Biochimica Et Biophysica Acta·Ronny HellandBjarni Asgeirsson

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