TY - JOUR
T1 - Multimerization of GPIHBP1 and Familial Chylomicronemia from a Serine-to-Cysteine Substitution in GPIHBP1's Ly6 Domain
AU - Plengpanich, Wanee
AU - Young, Stephen G
AU - Khovidhunkit, Weerapan
AU - Bensadoun, Andre
AU - Karnman, Hirankorn
AU - Ploug, Michael
AU - Gardsvoll, Henrik
AU - Leung, Calvin S
AU - Adeyo, Oludotun
AU - Larsson, Mikael
AU - Muanpetch, Suwanna
AU - Charoen, Supannika
AU - Fong, Loren G
AU - Niramitmahapanya, Sathit
AU - Beigneux, Anne P
N1 - Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
PY - 2014/7/11
Y1 - 2014/7/11
N2 - GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. GPIHBP1's ability to bind LPL depends on its Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in GPIHBP1's Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the pre-heparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, while wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in GPIHBP1's Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia.
AB - GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. GPIHBP1's ability to bind LPL depends on its Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in GPIHBP1's Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the pre-heparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, while wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in GPIHBP1's Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia.
U2 - 10.1074/jbc.M114.558528
DO - 10.1074/jbc.M114.558528
M3 - Journal article
C2 - 24847059
SN - 0021-9258
VL - 289
SP - 19491
EP - 19499
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
ER -