Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients

Omer An, Attila Gursoy, Aytemiz Gurgey, Ozlem Keskin

Research output: Contribution to journalArticlepeer-review

Abstract

Perforin plays a key role in the immune system via pore formation at the target cell membrane in the elimination of virus-infected and transformed cells. A vast number of observed mutations in perforin impair this mechanism resulting in a rare but fatal disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL2). Here we report a comprehensive in silico structural analysis of a collection of 76 missense perforin mutations based on a proposed pore model. In our model, perforin monomers oligomerize having cyclic symmetry in consistent with previously found experimental constraints yet having flexibility in the size of the pore and the number of monomers involved. Clusters of the mutations on the model map to three distinct functional regions of the perforin. Calculated stability (free energy) changes show that the mutations mainly destabilize the protein structure, interestingly however, A91V polymorphism, leads to a more stable one. Structural characteristics of mutations help explain the severe functional consequences on perforin deficient patients. Our study provides a structural approach to the mutation effects on the perforin oligomerization and impaired cytotoxic function in FHL2 patients.

Original languageEnglish
Pages (from-to)823-839
Number of pages17
JournalProtein Science
Volume22
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Familial hemophagocytic lymphohistiocytosis
  • FHL2
  • FHL2 patients
  • Perforin gene mutations
  • Structural analysis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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