G Arakelov

K Nazaryan

Pediatric Rheumatology

English

PubMed

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MEETING ABSTRACT Open AccessPW01-035 – Mutations in PB30.2D and complexingwith caspase-1K Nazaryan1,2, G Arakelov1*From 7th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)Lausanne, Switerland. 22-26 May 2013IntroductionMutations M680I, M694V and V726A of Pyrin - the pro-duct of MEFV gene - are localized at the domain B30.2(PB30.2D) and responsible for manifestation of the mostwidespread and severe forms of FMF. From the otherhand, it is well known that malfunction of the pyrin-cas-pase-1complex is the main reason for inflammation duringFMF. Therefore, we suggest that comparative investigationof normal and mutated pyrin and caspase-1 interactionwill help to reveal possible link between those mutationsand structural changes that influence formation of pyrin-caspase-1 complex.ObjectivesFrom abovementioned the goal of current study was todetect possible changes in the tertiary structure of B30.2and to show structural consequences that influence forma-tion of pyrin-caspase-1 complex.Methods3D structures of M680I, M694V and V726A was build upwith the help of Rosetta software, caspase-1and B30.2files obtained from PDB. Alignment of native B30.2 withthree mutant forms has been done by VMD programme.In silico molecular modeling interaction experimentsbetween native and mutated B30.2 and caspase-1 hasbeen performed by CHARMM software in in EffectiveEnergy Function 1 environment using 24-node computercluster. Each molecular modeling time was 110ns withiteration 2fs.ResultsInfluence of mutations on B30.2 tertiary structure hasrevealed the following structural changes: M680I –induces conversion of b-sheet into loop in positionTHR663-TRP665, loop - b-sheet in THR707- LEU710 andloop - a-helix in LYS765 – ALA768 site. Alignment ofthe native structure with mutation has RMSD=1,137 Å.M694V – conversion of the loop into b-sheet in the sitesLYS695-GLU696 and THR707 – LEU709, RMSD=1,699Å. V726A – conversion b-sheet into loop in the sitesTRP655 – VAL657, loop - b-sheet in THR707- LEU710and ARG725 – GLY727, loop - a-helix in ASP762 –LYS765, RMSD=1,808 Å. Molecular modeling of B30.2-caspase-1 dynamic interaction has shown significantdifferences between interaction energy of normal andmutated domains. Decrease in the minimal and averagecomplex formation energy in the case of V726A (71 and69% in comparison to the normal domain), no changes forM680I (99 and 97.4%) and increase for M694V (136.5 and126,5%). At the same time maximal energy values havenot shown any considerable differences.ConclusionSummarizing results of impact of the mutations on theB30.2-caspase-1 complex formation we came to the con-clusion that dramatic changes in the tertiary structureswhich reflected in the shifts of binding sites and differ-ences of interaction energy have notable influence onthe complex formation, which in its turn should affectprocess of IL1b activation a trigger stage of inflammationprocess.Disclosure of interestNone declared.Authors’ details1Russian-Armenian (Slavonic) University, Yerevan, Armenia. 2Institute ofMolecular Biology, Yerevan, Armenia.Published: 8 November 20131Russian-Armenian (Slavonic) University, Yerevan, ArmeniaFull list of author information is available at the end of the articleNazaryan and Arakelov Pediatric Rheumatology 2013, 11(Suppl 1):A88http://www.ped-rheum.com/content/11/S1/A88© 2013 Nazaryan and Arakelov; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.doi:10.1186/1546-0096-11-S1-A88Cite this article as: Nazaryan and Arakelov: PW01-035 – Mutations inPB30.2D and complexing with caspase-1. Pediatric Rheumatology 201311(Suppl 1):A88.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitNazaryan and Arakelov Pediatric Rheumatology 2013, 11(Suppl 1):A88http://www.ped-rheum.com/content/11/S1/A88Page 2 of 2

PW01-035 – Mutations in PB30.2D and complexing with caspase-1

http://dx.doi.org/10.1186/1546-0096-11-S1-A88

PW01-035 – Mutations in PB30.2D and complexing with caspase-1

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