Journal: Proc Natl Acad Sci U S A / Year: 2019 Title: Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis. Authors: Gabriel Birrane / Anne P Beigneux / Brian Dwyer / Bettina Strack-Logue / Kristian Kølby Kristensen / Omar L Francone / Loren G Fong / Haydyn D T Mertens / Clark Q Pan / Michael Ploug / ...Authors: Gabriel Birrane / Anne P Beigneux / Brian Dwyer / Bettina Strack-Logue / Kristian Kølby Kristensen / Omar L Francone / Loren G Fong / Haydyn D T Mertens / Clark Q Pan / Michael Ploug / Stephen G Young / Muthuraman Meiyappan / Abstract: Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three- ...Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in or cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.
A: Lipoprotein lipase B: Lipoprotein lipase C: Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 D: Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 hetero molecules
Mass: 50379.016 Da / Num. of mol.: 2 / Fragment: UNP residues 28-475 / Mutation: R324A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: LPL, LIPD / Plasmid: pZ804N / Cell line (production host): HT1080 / Production host: Homo sapiens (human) / Tissue (production host): Connective tissue / References: UniProt: P06858, lipoprotein lipase
#2: Protein
Glycosylphosphatidylinositol-anchoredhighdensitylipoprotein-bindingprotein1 / GPIHBP1 / GPI-anchored HDL-binding protein 1 / High density lipoprotein-binding protein 1
Mass: 14725.788 Da / Num. of mol.: 2 / Fragment: UNP residues 21-151 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GPIHBP1, HBP1 / Plasmid: pFastbac-1 / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8IV16
Resolution: 2.8→48.41 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.936 / SU B: 35.926 / SU ML: 0.295 / Cross valid method: THROUGHOUT / ESU R: 0.859 / ESU R Free: 0.32 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
Rfactor
Num. reflection
% reflection
Selection details
Rfree
0.23545
1833
4.9 %
RANDOM
Rwork
0.19534
-
-
-
obs
0.19738
35568
99.23 %
-
Solvent computation
Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å