Impaired dimer assembly and decreased stability of naturally recurring R260C mutant A subunit for coagulation factor XIII

Maeda, Siro; Zhang, Wei Guang; Souri, Masayoshi; Yee, Vivien C.; Ichinose, Akitada

doi:10.1093/jb/mvs088

Cited by 10 publications

(13 citation statements)

References 34 publications

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“…Previously only five FXIIIB mutations, including only one missense mutation, were reported. To date, there have been several expression-based analytical studies for mutations associated with severe FXIII deficiency [Balogh et al, 2000;Hettasch and Greenberg, 1994;Maeda et al, 2012;Mikkola et al, 1997;Vysokovsky et al, 2006;Wang et al, 2011;Zheng et al, 2011]. However, only one of these investigated a FXI-IIB missense mutation that was at that time the only one known and that causes mild-to-moderate FXIII deficiency [Hashiguchi and Ichinose, 1995;Saito et al, 1990].…”

Section: Introductionmentioning

confidence: 99%

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Biswas¹,

Thomas²,

Bevans

et al. 2013

Human Mutation

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Coagulation factor XIII (FXIII) proenzyme circulates in plasma as a heterotetramer composed of two each of A and B subunits. Upon activation, the B subunits dissociate from the A subunit dimer, which gains transglutaminase activity to cross-link preformed fibrin clots increasing mechanical strength and resistance to degradation. The B subunits are thought to possess a carrier/protective function before FXIII activation. Mutations in either A or B subunits are associated with pathological patient phenotypes characterized by mild to severe bleeding. In vitro expression of FXIII B subunit (FXIIIB) missense variants in HEK293T cells revealed impaired secretion for all seven variants studied. To investigate the likely molecular environments of the missense residues, we created molecular models of individual FXIIIB Sushi domains using phylogenetically similar complement factor H Sushi domain structural templates. Assessment of the local molecular environments for the models suggested surface or buried positions for each mutant residue and possible pathological mechanisms. The in vitro expression system and in silico analytical methods and models we developed can be used to further investigate the molecular basis of FXIIIB mutation pathologies.

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Section: Introductionmentioning

confidence: 99%

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Biswas¹,

Thomas²,

Bevans

et al. 2013

Human Mutation

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show abstract

“…13 Molecular modeling also suggested that these four mutations would weaken intersubunit interactions and dimerization. [10][11][12]14 Further mutations localized at the interface of the A 2 -dimer have been identified in congenital FXIII deficiency, but these have not been further characterized by expression and biochemical studies, so it can only be speculated that they may also interfere with dimer formation.…”

Section: What Holds the A Subunits Together In The Factor Xiii-a 2 DImentioning

confidence: 99%

Factor XIII: Structure and Function

Schroeder

Köhler

2016

Semin Thromb Hemost

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Over the last two decades, it became evident that factor XIII (FXIII) is not only a crucial determinant of clot characteristics but also has potentially important functions in many various fields such as bone biology, immunity, and adipogenesis. In this review, we aim to summarize the latest findings regarding structure and function of FXIII. In regard to FXIII structure, much progress has been made recently to understand how its subunits are held together. In the A subunit, the activation peptide has a crucial role in the formation of FXIII-A2 dimers. In the B subunit, Sushi domains that are involved in binding to the A subunit and in B2 dimer formation have been identified. In regard to FXIII function, interactions with immune cells and the complement system have been described. A novel function of FXIII-A in adipogenesis has been suggested. The role of FXIII-A in osteoblast differentiation has been further investigated; however, a novel double knockout mouse deficient in both FXIII-A and transglutaminase 2 showed normal bone formation. Thus, more research, in particular, into the cellular functions of FXIII-A is still required.

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“…Expression in BHKcells resulted in rapid degradation. R260C expressed in yeast, subjected to gel filtration, and was concluded to be a monomer (75)(76)(77).…”

Section: R260cmentioning

confidence: 99%

“…Certain single amino acid substitutions were previously predicted to impair dimerization of the zymogen FXIIIA form (74)(75)(76)(77)(78)(79). To obtain solution evidence of such impairment in the current work, the expression of these mutants was attempted in E. coli.…”

Section: Fxiiia Mutants With Proposed Impaired Dimerizationmentioning

confidence: 99%

“…Activation peptide substitution R11Q was computationally predicted to impair A2 dimer formation. Most of those mutants were unstable in eukaryotic expression systems (74)(75)(76)(77)(78)(79). Recombinant expression in E. coli along with affinity purification could be more feasible for obtaining mutant proteins, however, this approach had not been attempted before.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coagulation Factor XIIIA: biochemical properties underlying physiological function.

Anokhin¹

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Impaired dimer assembly and decreased stability of naturally recurring R260C mutant A subunit for coagulation factor XIII

Cited by 10 publications

References 34 publications

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

Factor XIII: Structure and Function

Coagulation Factor XIIIA: biochemical properties underlying physiological function.

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