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Hum Mol Genet. 2016 Mar 15;25(6):1233-46. doi: 10.1093/hmg/ddw004. Epub 2016 Jan 10.

Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.

Author information

1
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain, Biocomputation and Complex Systems Physics Institute (BIFI), Joint Unit BIFI-IQFR (CSIC), Universidad de Zaragoza, Mariano Esquillor, Edificio I + D, 50018 Zaragoza, Spain.
2
Institut de Recerca Biomèdica (IRB Barcelona), Baldiri Reixac 10-12, 08028 Barcelona, Spain, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Diagonal 643, 08028 Barcelona, Spain, Joint BSC-CRG-IRB Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain, and.
3
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain, Biocomputation and Complex Systems Physics Institute (BIFI), Joint Unit BIFI-IQFR (CSIC), Universidad de Zaragoza, Mariano Esquillor, Edificio I + D, 50018 Zaragoza, Spain, Aragon Institute for Health Research (IIS Aragón), Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain jsancho@unizar.es.

Abstract

Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH.

PMID:
26755827
PMCID:
PMC4764198
DOI:
10.1093/hmg/ddw004
[Indexed for MEDLINE]
Free PMC Article

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