Bioinformatic analysis of protein structure-function relationships: case study of leukocyte elastase (ELA2) missense mutations.
Thusberg, Janita and Vihinen, Mauno LU
(2006)
In Human Mutation
27(12).
p.1230-1243
- Abstract
- Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic... (More)
- Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3635345
- author
- Thusberg, Janita
and Vihinen, Mauno
LU
- publishing date
- 2006
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Computational Biology: methods, Enzyme Stability: genetics, Leukocyte Elastase: chemistry, Leukocyte Elastase: genetics, Sequence Alignment: methods
- in
- Human Mutation
- volume
- 27
- issue
- 12
- pages
- 1230 - 1243
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:16986121
- scopus:33750971454
- ISSN
- 1059-7794
- DOI
- 10.1002/humu.20407
- language
- English
- LU publication?
- no
- id
- 2f893bb9-31c5-4bdc-965e-b6ff6d8411d0 (old id 3635345)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/16986121?dopt=Abstract
- date added to LUP
- 2016-04-04 07:08:03
- date last changed
- 2022-01-29 01:44:16
@article{2f893bb9-31c5-4bdc-965e-b6ff6d8411d0,
abstract = {{Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.}},
author = {{Thusberg, Janita and Vihinen, Mauno}},
issn = {{1059-7794}},
keywords = {{Computational Biology: methods; Enzyme Stability: genetics; Leukocyte Elastase: chemistry; Leukocyte Elastase: genetics; Sequence Alignment: methods}},
language = {{eng}},
number = {{12}},
pages = {{1230--1243}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Human Mutation}},
title = {{Bioinformatic analysis of protein structure-function relationships: case study of leukocyte elastase (ELA2) missense mutations.}},
url = {{http://dx.doi.org/10.1002/humu.20407}},
doi = {{10.1002/humu.20407}},
volume = {{27}},
year = {{2006}},
}