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标题：Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene
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作者：Jonas Peterson ; Amir F. Ayyobi ; Yuanhong Ma 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2002
卷号：43
期号：3
页码：398-406
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly¹⁸⁸→Glu LPL and the stable Ile¹⁹⁴→Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile¹⁹⁴→Thr substitution interferes with access of lipid substrate to the catalytic pocket. These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis. —Peterson, J., A. F. Ayyobi, Y. Ma, H. Henderson, M. Reina, S. S. Deeb, S. Santamarina-Fojo, M. R. Hayden, and J. D. Brunzell. Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. J. Lipid Res. 2002. 43: 398–406.
关键词：LPL deficiency ; triglyceride ; heparin ; LPL gene ; LPL mass