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Arg260‐Cys mutation in severe factor XIII deficiency: conformational change of the A subunit is predicted by molecular modelling and mechanics
Author(s) -
Ichinose Akitada,
Tsukamoto Hiroaki,
Izumi Tomonori,
Yamazaki Tomio,
Togashi Masaki,
Takamatsu Junki,
Saito Hidehiko,
Umeyama Hideaki
Publication year - 1998
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1998.00698.x
Subject(s) - salt bridge , protein subunit , dimer , mutation , genetics , coding region , chemistry , molecular mechanics , null allele , gene , mutant , microbiology and biotechnology , stereochemistry , molecular dynamics , biology , computational chemistry , organic chemistry
To explore the implications of the structure/function relationships in factor XIII, a patient with severe A subunit deficiency was examined at the DNA and RNA levels. Nucleotide sequence analysis of the patient's DNA amplified by PCR revealed that the patient had a replacement of C by T in the codon for Arg260. RT‐PCR analysis demonstrated that only one kind of mRNA coding for the Arg260‐Cys mutation was expressed in the patient at a normal level. Another possible defective allele of the A subunit gene with a G‐A polymorphism was not expressed (null allele). The substitution of Arg260 by Cys located on the interface of two A subunits would preclude the reciprocal ionic interaction (salt bridge) between Arg260 and Asp404. Molecular modelling and, for the first time, molecular mechanics calculated that Cys260 changed the local conformation of the A subunit and reduced the electrostatic interaction between two monomers, suggesting destabilization of the molecule's dimer.