Characterization of the role of EGF-A of low density lipoprotein receptor in PCSK9 binding

Proprotein convertase subtilisin kexin-like 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR) and plays an important role in regulating plasma LDL-cholesterol levels. We have shown that the epidermal growth factor precursor homology domain A (EGF-A) of the LDLR is critical for PCSK9 binding at the cell surface (pH 7.4). Here, we further characterized the role of EGF-A in binding of PCSK9 to the LDLR. We found that PCSK9 efficiently bound to the LDLR but not to other LDLR family members. Replacement of EGF-A in the very low density lipoprotein receptor (VLDLR) with EGF-A of the LDLR promoted the degradation of the mutant VLDLR induced by PCSK9. Furthermore, we found that PCSK9 bound to recombinant EGF-A in a pH-dependent manner with stronger binding at pH 6.0. We also identified amino acid residues in EGF-A of the LDLR important for PCSK9 binding. Mutations G293H, D299V, L318D, and L318H reduced PCSK9 binding to the LDLR at neutral pH without effect at pH 6.0, while mutations R329P and E332G reduced PCSK9 binding at both pH values. Thus, our findings reveal that EGF-A of the LDLR is critical for PCSK9 binding at the cell surface (neutral pH) and at the acidic endosomal environment (pH 6.0), but different determinants contribute to efficient PCSK9 binding in different pH environments. Proprotein convertase subtilisin kexin-like 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR) and plays an important role in regulating plasma LDL-cholesterol levels. We have shown that the epidermal growth factor precursor homology domain A (EGF-A) of the LDLR is critical for PCSK9 binding at the cell surface (pH 7.4). Here, we further characterized the role of EGF-A in binding of PCSK9 to the LDLR. We found that PCSK9 efficiently bound to the LDLR but not to other LDLR family members. Replacement of EGF-A in the very low density lipoprotein receptor (VLDLR) with EGF-A of the LDLR promoted the degradation of the mutant VLDLR induced by PCSK9. Furthermore, we found that PCSK9 bound to recombinant EGF-A in a pH-dependent manner with stronger binding at pH 6.0. We also identified amino acid residues in EGF-A of the LDLR important for PCSK9 binding. Mutations G293H, D299V, L318D, and L318H reduced PCSK9 binding to the LDLR at neutral pH without effect at pH 6.0, while mutations R329P and E332G reduced PCSK9 binding at both pH values. Thus, our findings reveal that EGF-A of the LDLR is critical for PCSK9 binding at the cell surface (neutral pH) and at the acidic endosomal environment (pH 6.0), but different determinants contribute to efficient PCSK9 binding in different pH environments. Familial hypercholesterolemia (FH) is a common genetic disorder characterized by high cholesterol levels, specifically very high low density lipoprotein (LDL), and increased risk of coronary heart disease and mortality. The main cause of FH is the mutations in the LDL receptor (LDLR) gene (1Goldstein J.L. Hobbs H.H. Brown M.S. et al.Familial hypercholesterolemia..in: Scriver C.R. Beaudet A.L. Sly W.S. In The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York2001: 2863-2913Google Scholar). Most recently, mutations in the proprotein convertase subtilisin kexin-like 9 (PCSK9) genes have been found to be linked with FH (2Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref D. S. M. M. Devillers M. M. J.P. et mutations of the PCSK9 gene cause of autosomal dominant Mutations in the PCSK9 gene in with autosomal dominant Genet. S. K. S. A in PCSK9 hypercholesterolemia in a Genet. Hobbs H.H. for a Scholar). mutations cause plasma LDL-cholesterol and to and coronary heart disease (2Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref D. S. M. M. Devillers M. M. J.P. et mutations of the PCSK9 gene cause of autosomal dominant Mutations in the PCSK9 gene in with autosomal dominant Genet. S. K. S. A in PCSK9 hypercholesterolemia in a Genet. M. Rabes J.P. Devillers M. Erlich D. C. Varret M. C. Mutations and in the proprotein convertase subtilisin 9 (PCSK9) gene in cholesterol and Scholar). the other mutations in low of and coronary heart disease Hobbs H.H. LDL cholesterol in of mutations in Genet. Hobbs H.H. in low and coronary heart in low LDL and risk of Hobbs H.H. A of PCSK9 to plasma of lipoprotein Genet. The in PCSK9 is and cholesterol in a The proprotein and in L. Hobbs H.H. Molecular of mutations in PCSK9 and of a Genet. M. Rabes J.P. S. Varret M. S. et of hypercholesterolemia in of LDLR mutations and role of PCSK9 a Scholar). PCSK9 is a amino acid that of a amino acid by a a and a The role of PCSK9 in of plasma is degradation of the of by the PCSK9 the of LDL in and in of M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Hobbs H.H. for degradation of the lipoprotein of mutations in the PCSK9 gene the cell surface LDL Genet. J.L. of PCSK9 the degradation of the LDLR in a of low density lipoprotein receptor by proprotein convertase in Scholar). plasma of PCSK9 in of PCSK9 in the LDLR degradation in the but not in the PCSK9 LDL in L. D. S. and of PCSK9 in Scholar). the other of PCSK9 in to increased of LDLR in the and LDL S. plasma cholesterol and to in M. D. K. et PCSK9 plasma cholesterol in and LDL cholesterol in Scholar). in and that PCSK9 LDLR degradation PCSK9 the of LDL in and in of M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Hobbs H.H. for degradation of the lipoprotein of mutations in the PCSK9 gene the cell surface LDL Genet. Scholar). of PCSK9 in and also LDLR degradation J.L. of PCSK9 the degradation of the LDLR in a of low density lipoprotein receptor by proprotein convertase in Scholar). LDLR degradation binding of PCSK9 to the LDLR and of the but not the of PCSK9 PCSK9 the of LDL in and in of M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and is not for PCSK9 to low density lipoprotein in Scholar). Most recently, been shown that of the LDLR and the endosomal for not for LDLR degradation Hobbs H.H. Molecular of proprotein convertase degradation of the Scholar). We have shown that PCSK9 with the epidermal growth factor precursor homology domain A (EGF-A) of the LDLR at the cell surface and to the receptor with a in the acidic environment of the the receptor the to the for M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). the of PCSK9 and the of the LDLR reveal that the of EGF-A is with the domain of PCSK9 Molecular for LDL receptor by L. L. et and of the and hypercholesterolemia S. for LDL receptor degradation the at neutral Scholar). We also that at in EGF-A of the LDLR is critical for efficient binding of PCSK9 M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). The of in the LDLR with is in the very low density lipoprotein receptor binding of PCSK9 to the LDLR. we further characterized the role of EGF-A of the LDLR in PCSK9 binding to the We found that and in EGF-A of the LDLR to PCSK9 binding at the cell We also found that PCSK9 bound to recombinant EGF-A in a pH-dependent with a stronger binding at pH 6.0. and cell and The other The recombinant PCSK9 mutant PCSK9 a at the of an amino acid in critical for cholesterol of of binding effect and Scholar). The domain of the LDLR a at the and L. K. K. Brown M.S. J.L. of the LDL receptor domain at endosomal Scholar). and PCSK9 with and to the and the an A recombinant the LDLR linked to to the mutant of the LDLR the to the The VLDLR and low density lipoprotein of a at the The the residues to be by The of the and the of by The binding M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). in at and in with for receptor to the with in of and PCSK9 for The and in of cell to an for the J.L. Brown M.S. of the low density lipoprotein receptor by the PCSK9 PCSK9 the of LDL in and in of to the and to and binding by The to binding The by a The degradation Hobbs H.H. for degradation of the lipoprotein Scholar). the cell in at and in with for mutant LDLR VLDLR to the in of and of mutant PCSK9 for the with and in of by and a EGF-A of the LDLR recombinant the in and M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). the at induced with and The a The to the The and further a a by and The with M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). and with The to The and with in pH (pH and the at for with PCSK9 in the pH by with pH The by a The in K. the domain of the LDL receptor and the domain of PCSK9 is for PCSK9 to bound to the LDL receptor endosomal Genet. with in with for mutant LDLR and the with pH and (pH and for in pH The with pH PCSK9 for at with pH without and in of The cell to and The LDLR and PCSK9 with for mutant LDLR cell surface of an amino acid in critical for cholesterol Scholar). The in of and to at for A of of the cell and of the to of of The at at for the in for at The cell surface the by (pH and and for at by and by to the is We have that PCSK9 efficiently to the LDLR but not to the VLDLR M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). The residues and in EGF-A an important role in PCSK9 binding. M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). and the binding in EGF-A S. of the LDL receptor a for the of binding Scholar). of EGF-A in LDLR family that is in we and and is in LDLR Thus, we LDLR family in and to PCSK9. to PCSK9 binding to the LDLR PCSK9 to the LDLR but the degradation of the receptor in cell Hobbs H.H. Molecular of role in LDL Scholar). In LDLR in is PCSK9 binding. The of different LDLR family by shown in PCSK9 to the and with the for at (pH the PCSK9 in LDLR but not in other LDLR family we EGF-A of the LDLR to receptor We have that in EGF-A of the VLDLR is with EGF-A of the to PCSK9 very binding of PCSK9 to in EGF-A of the LDLR is by EGF-A the is reduced M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). the in and with PCSK9 for at pH The VLDLR that a at by an both the precursor and the of the receptor We that of PCSK9 in degradation of the of and the LDLR VLDLR and the not be by PCSK9. Thus, EGF-A of the LDLR is to degradation of a is in a cell surface that not PCSK9 been that PCSK9 promotes the degradation of both VLDLR and S. Benjannet S. The proprotein convertase PCSK9 the degradation of low density lipoprotein receptor (LDLR) and family VLDLR and Scholar). the our findings and we the VLDLR and the LDLR in and the with of PCSK9 mutant PCSK9 for and at pH The of PCSK9 in plasma to Hobbs H.H. and determinants of plasma PCSK9 Scholar). Thus, the of PCSK9 we to We that with the for PCSK9 not efficiently VLDLR at a of but efficiently promoted LDLR degradation at a of that to the LDLR with a VLDLR degradation efficiently at a of with the for findings that the VLDLR be by but with with the LDLR. We have that of in EGF-A of the LDLR with is in the PCSK9 binding M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). of EGF-A of the LDLR that the is different for a at that we the of in EGF-A of the LDLR for efficient PCSK9 binding. to other amino a is in the a is in a is in a neutral amino acid is in and a is in the LDLR and a mutant LDLR PCSK9 to the (pH 7.4). The of PCSK9 we in the the PCSK9 in plasma Hobbs H.H. and determinants of plasma PCSK9 Scholar). shown in the to the LDLR both the precursor and the of the of LDLR in with PCSK9 found with the the mutant mutant LDLR in EGF-A in the LDLR with EGF-A the VLDLR with our findings M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). Replacement of with also to PCSK9 of to the to of with a PCSK9 binding with the we that the of amino acid at in EGF-A of LDLR plays an important role in PCSK9 binding at the cell Replacement of with PCSK9 while reduced PCSK9 that the the amino acid at in EGF-A of the LDLR PCSK9 binding to the receptor at the cell Thus, we the of in the amino acid at other in EGF-A of the LDLR PCSK9 binding. We amino acid residues in EGF-A that different the LDLR and the shown in amino acid residues different the LDLR and the residues the amino acid We amino acid residues in the LDLR with residues in the VLDLR The residues of and in the VLDLR and not the the amino acid and to and in FH Thus, we also the effect of FH mutations PCSK9 binding. PCSK9 to mutant LDLR and with the for at (pH 7.4). of LDLR PCSK9 binding of PCSK9 to the mutant R329P and E332G while binding of PCSK9 to increased mutations effect PCSK9 binding. Thus, and also in PCSK9 binding to the LDLR. We have shown that PCSK9 with EGF-A of the LDLR at the cell surface and to the receptor with a in the acidic environment of the the receptor is to the for degradation M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). Most recently, been shown that the domain of PCSK9 with the binding of the LDLR acidic K. the domain of the LDL receptor and the domain of PCSK9 is for PCSK9 to bound to the LDL receptor endosomal Genet. C. A binding of PCSK9 with the low density lipoprotein contribute to the stronger binding PCSK9 and the LDLR in the we PCSK9 bound to recombinant EGF-A in a pH-dependent EGF-A and shown a of that the domain of the LDLR and to The and with PCSK9 at different pH values. shown in PCSK9 bound to the in a pH-dependent The binding stronger at pH with PCSK9 the of LDL in and in of M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). PCSK9 binding to at pH The binding of PCSK9 to to that of the binding at pH we binding of PCSK9 to different of and at pH and pH 6.0. The of PCSK9 binding and the of the to a binding The of PCSK9 binding to at pH and at pH and for pH and pH 6.0, The of PCSK9 binding to at pH and at pH and We also the binding with the in The and of PCSK9 binding to and for pH and and for pH 6.0, Thus, PCSK9 increased the recombinant at pH 6.0. We the effect of mutations in EGF-A of the LDLR PCSK9 binding to the receptor in an acidic The binding at and pH to the of the LDLR and to PCSK9 binding in the endosomal been to binding and binding K. the domain of the LDL receptor and the domain of PCSK9 is for PCSK9 to bound to the LDL receptor endosomal Genet. C. of the lipoprotein receptor binding and C. and low lipoprotein by the LDL Scholar). mutant LDLR with pH (pH PCSK9 for at PCSK9 and the LDLR in the cell by We found that mutations R329P and E332G to a in PCSK9 binding at pH 6.0. mutations and that PCSK9 binding at pH effect PCSK9 binding at pH 6.0. of to also effect PCSK9 binding at pH mutations PCSK9 binding at pH that mutations R329P and E332G reduced PCSK9 binding at both pH we the mutations the cell surface of the LDLR the with The cell surface and for the LDLR. shown in the cell surface of and mutant LDLR to the of of the in the cell that the mutations effect the of the LDLR to the plasma that mutations D299V, G293H, and in EGF-A PCSK9 binding at pH but not at pH 6.0, that residues not contribute to PCSK9 binding in the acidic endosomal that to the LDLR with a in the M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and other of the LDLR contribute to PCSK9 binding at the low pH been shown to with the of PCSK9 S. for LDL receptor degradation the at neutral Scholar). We have that the LDLR but be to degradation Hobbs H.H. for degradation of the lipoprotein Scholar). The of the LDLR at the low pH that and pH to of the receptor acidic L. K. K. Brown M.S. J.L. of the LDL receptor domain at endosomal Scholar). Thus, we to to and to to the role of residues in the LDLR. The mutant receptor in at a the receptor and of PCSK9 to the in a in and mutant LDLR and In been that and in an role in the of the LDLR C. and low lipoprotein by the LDL Scholar). we also and the LDLR. and by and and the in shown in mutations effect degradation of the LDLR. Thus, the residues and the residues not for degradation of the LDLR. The for the critical role of EGF-A of the LDLR in degradation of the PCSK9 efficiently bound to the LDLR the LDLR family we EGF-A the LDLR to VLDLR degradation of PCSK9 at a PCSK9 not VLDLR degradation at a of with In we that PCSK9 bound to recombinant EGF-A in a pH-dependent manner with binding at pH Replacement of amino acid residues and in EGF-A of the LDLR with residues in the VLDLR reduced PCSK9 binding at pH without PCSK9 binding at pH the other of with amino acid residues in the VLDLR and FH reduced PCSK9 binding at pH and we that residues in and in and residues and in an important role in the of LDL the not for the LDLR we have that the of PCSK9 with is in the but not in the VLDLR of PCSK9 at a M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). Most recently, et L. L. PCSK9 to and be by an EGF-A and et S. Benjannet S. The proprotein convertase PCSK9 the degradation of low density lipoprotein receptor (LDLR) and family VLDLR and that PCSK9 to the VLDLR and the is that binding of PCSK9 to the VLDLR be to be in our we a of PCSK9 to Thus, in the we LDLR family with the of PCSK9 for we PCSK9 binding in the LDLR but not in other LDLR family the VLDLR and the The different be for by the different in We for with the that we the of et S. Benjannet S. The proprotein convertase PCSK9 the degradation of low density lipoprotein receptor (LDLR) and family VLDLR and in the PCSK9. et L. L. PCSK9 to and be by an EGF-A an in by and PCSK9 different we the the VLDLR with of and mutant PCSK9 for We that mutant that a for the but not induced VLDLR degradation at a of PCSK9 not the degradation of mutant LDLR in EGF-A by EGF-A of VLDLR but promoted the degradation of mutant in EGF-A with EGF-A of LDLR that PCSK9 VLDLR but with with the LDLR. The VLDLR and M. M. of in the receptor and receptor Scholar). Most recently, et C. K. proprotein convertase 9 (PCSK9) VLDLR and in that PCSK9 VLDLR degradation in cell surface of VLDLR and C. K. proprotein convertase 9 (PCSK9) VLDLR and in Scholar). of PCSK9 in is not with for L. Hobbs H.H. Molecular of mutations in PCSK9 and of a Genet. S. plasma cholesterol and to in Scholar). The for the different in and in is The homology and VLDLR is with amino acid The PCSK9 and LDLR the domain of PCSK9 and EGF-A of the LDLR S. for LDL receptor degradation the at neutral Scholar). EGF-A of the VLDLR is in and Most recently, et S. for LDL receptor degradation the at neutral that the of PCSK9 with the domain of the LDLR is amino acid in and to different amino acid residues PCSK9 binding to the findings that the role of PCSK9 to VLDLR is The plasma of PCSK9 in without to Hobbs H.H. and determinants of plasma PCSK9 Scholar). been shown that plasma of PCSK9 increased in with M. M. M. PCSK9 by and in of proprotein convertase Scholar). Thus, is that PCSK9 VLDLR degradation in with high plasma of PCSK9 PCSK9 while we that of in the LDLR with is in the PCSK9 and of the in the VLDLR to PCSK9 binding M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). Here, we that of in LDLR with is in the increased PCSK9 binding. of the in the VLDLR to in the effect PCSK9 binding M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). that at of EGF-A of the LDLR plays a critical role in binding of PCSK9 to the we found that of in EGF-A of the LDLR with other residues and in and reduced PCSK9 binding. of with is in PCSK9 binding of EGF-A of LDLR family that EGF-A in amino acid residues that for binding of PCSK9 and M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). binding in that be other determinants in EGF-A of the LDLR that contribute to efficient PCSK9 binding. We that in to of and in EGF-A of the LDLR with amino acid residues in the VLDLR reduced PCSK9 binding at pH and at the cause binding of PCSK9. PCSK9 to the LDLR in a pH-dependent manner with a at low that the binding in the LDLR with the of PCSK9 at low pH and contribute a to PCSK9 in the acidic endosomal In the we that PCSK9 bound to EGF-A at pH at pH binding that binding of PCSK9 to recombinant increased at pH 6.0, with findings that the pH binding environment to a in the binding of the recombinant to with pH Molecular for LDL receptor by Scholar). findings that EGF-A also to the PCSK9 and the LDLR at the acidic environment of the mutations and reduced PCSK9 binding at pH but effect PCSK9 binding at pH 6.0, and PCSK9 binding at pH EGF-A bound to PCSK9 at pH that determinants in EGF-A of the LDLR for efficient PCSK9 binding different at different pH environments. The of the at neutral and low pH Molecular for LDL receptor by L. L. et and of the and hypercholesterolemia Scholar). for EGF-A L. L. et and of the and hypercholesterolemia Scholar). in EGF-A of the LDLR an with at neutral pH L. L. et and of the and hypercholesterolemia but an with in PCSK9 at pH Molecular for LDL receptor by Scholar). Thus, is that the of the neutral pH to acidic pH in the to in in different amino acid residues in EGF-A in PCSK9 binding at an acidic residues contribute to PCSK9 binding at pH 6.0, but the other of the the binding also with PCSK9 at the acidic endosomal environment K. the domain of the LDL receptor and the domain of PCSK9 is for PCSK9 to bound to the LDL receptor endosomal Genet. C. A binding of PCSK9 with the low density lipoprotein for the of residues in EGF-A at pH 6.0. and C. A binding of PCSK9 with the low density lipoprotein a binding for PCSK9 and the LDLR. The domain of PCSK9 with EGF-A of the LDLR at the cell The of the LDLR is the receptor is to the low pH endosomal The binding of the LDLR with the of PCSK9 binding at the acidic endosomal been shown that in and and in pH to of the receptor acidic L. K. K. Brown M.S. J.L. of the LDL receptor domain at endosomal and an important role in the of bound LDL C. and low lipoprotein by the LDL Scholar). of the LDLR also with the of PCSK9 S. for LDL receptor degradation the at neutral and is for LDLR degradation Hobbs H.H. for degradation of the lipoprotein Scholar). the of LDL binding and of to to and to of the and in to effect LDLR that residues have in the FH PCSK9 binding C. of PCSK9 lipoprotein receptor in Scholar). Here, we found that FH effect PCSK9 binding while R329P reduced PCSK9 binding at pH and 6.0. The of that R329P the of the of the binding in EGF-A S. of the LDL receptor a for the of binding Scholar). The of the in EGF-A is important for PCSK9 binding M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Scholar). Thus, R329P PCSK9 binding of the in EGF-A of the LDLR. The of reveal that PCSK9 with the EGF-A Molecular for LDL receptor by L. L. et and of the and hypercholesterolemia S. for LDL receptor degradation the at neutral Scholar). a to the of in PCSK9. We found that reduced PCSK9 binding. et L. M. C. et of PCSK9 by of the LDL that of with in recombinant EGF-A effect PCSK9 binding. Thus, is that D299V, but not the to in to a in PCSK9 binding. to PCSK9 binding a to in PCSK9. Replacement of with PCSK9 binding at pH with the that of with a in recombinant EGF-A binding for PCSK9 L. M. C. et of PCSK9 by of the LDL Scholar). a in the that the the of in the to in PCSK9. Thus, PCSK9 binding. The of and a with in PCSK9 Molecular for LDL receptor by Scholar). of to also a in the the of in PCSK9 binding. The of in PCSK9 is by in EGF-A a at low pH L. L. et and of the and hypercholesterolemia Scholar). Thus, mutations and not PCSK9 binding at pH is the amino acid in the of PCSK9 with the EGF-A and not with the of is the amino acid in also not with PCSK9. Thus, is that and contribute to binding of PCSK9 to the LDLR effect PCSK9 binding at pH and E332G effect the of the LDLR to the cell that the mutations not in a of the of the we a that the mutations cause in PCSK9 binding In we characterized the role of EGF-A of the LDLR in PCSK9 binding and identified amino acid residues in EGF-A that contribute to PCSK9 binding. we found that mutations and increased PCSK9 binding. and reveal that EGF-A with PCSK9 M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Molecular for LDL receptor by L. L. et and of the and hypercholesterolemia Scholar). of the LDLR and EGF-A LDLR degradation in L. L. et and of the and hypercholesterolemia L. L. PCSK9 to and be by an EGF-A C. of PCSK9 lipoprotein receptor in Scholar). in and that PCSK9 LDLR degradation PCSK9 the of LDL in and in of M. Hobbs H.H. of proprotein convertase 9 to epidermal growth A of low density lipoprotein receptor receptor and Hobbs H.H. for degradation of the lipoprotein of mutations in the PCSK9 gene the cell surface LDL Genet. Scholar). the EGF-A domain that amino acid residues is a very for LDLR EGF-A to PCSK9 with a low Thus, the of mutations in EGF-A that PCSK9 binding a to EGF-A that to PCSK9 with a high The to and Hobbs of at for and The also for and for in receptor epidermal growth factor precursor homology domain A hypercholesterolemia LDL-cholesterol low density lipoprotein receptor domain of the LDL receptor low density lipoprotein proprotein convertase subtilisin kexin-like 9 very low density lipoprotein receptor

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.