Key points are not available for this paper at this time.
ARH is an adaptor protein required for efficient endocytosis of low density lipoprotein (LDL) receptors (LDLRs) in selected tissues. Individuals lacking ARH (ARH-/-) have severe hypercholesterolemia due to impaired hepatic clearance of LDL. Immortalized lymphocytes, but not fibroblasts, from ARH-deficient subjects fail to internalize LDL. To further define the role of ARH in LDLR function, we compared the subcellular distribution of the LDLR in lymphocytes from normal and ARH-/- subjects. In normal lymphocytes LDLRs were predominantly located in intracellular compartments, whereas in ARH-/- cells the receptors were almost exclusively on the plasma membrane. Biochemical assays and quantification of LDLR by electron microscopy indicated that ARH-/- lymphocytes had >20-fold more LDLR on the cell surface and a ∼27-fold excess of LDLR outside of coated pits. The accumulation of LDLR on the cell surface was not due to failure of receptors to localize in coated pits since the number of LDLRs in coated pits was similar in ARH-/- and normal cells. Despite the dramatic increase in cell surface receptors, LDL binding was only 2-fold higher in the ARH-/- lymphocytes. These findings indicate that ARH is required not only for internalization of the LDL·LDLR complex but also for efficient binding of LDL to the receptor and suggest that ARH stabilizes the associations of the receptor with LDL and with the invaginating portion of the budding pit, thereby increasing the efficiency of LDL internalization. ARH is an adaptor protein required for efficient endocytosis of low density lipoprotein (LDL) receptors (LDLRs) in selected tissues. Individuals lacking ARH (ARH-/-) have severe hypercholesterolemia due to impaired hepatic clearance of LDL. Immortalized lymphocytes, but not fibroblasts, from ARH-deficient subjects fail to internalize LDL. To further define the role of ARH in LDLR function, we compared the subcellular distribution of the LDLR in lymphocytes from normal and ARH-/- subjects. In normal lymphocytes LDLRs were predominantly located in intracellular compartments, whereas in ARH-/- cells the receptors were almost exclusively on the plasma membrane. Biochemical assays and quantification of LDLR by electron microscopy indicated that ARH-/- lymphocytes had >20-fold more LDLR on the cell surface and a ∼27-fold excess of LDLR outside of coated pits. The accumulation of LDLR on the cell surface was not due to failure of receptors to localize in coated pits since the number of LDLRs in coated pits was similar in ARH-/- and normal cells. Despite the dramatic increase in cell surface receptors, LDL binding was only 2-fold higher in the ARH-/- lymphocytes. These findings indicate that ARH is required not only for internalization of the LDL·LDLR complex but also for efficient binding of LDL to the receptor and suggest that ARH stabilizes the associations of the receptor with LDL and with the invaginating portion of the budding pit, thereby increasing the efficiency of LDL internalization. The low density lipoprotein receptor (LDLR) 1The abbreviations used are: LDLR, low density lipoprotein receptor; LDR, low density lipoprotein; EEA, early endosome antigen; β-VLDL, β-migrating very low density lipoprotein; apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; PTB, phosphotyrosine binding. mediates the rapid endocytosis of apolipoprotein (apo) B-containing lipoproteins. Internalization of the LDLR occurs via clathrin-coated pits and is mediated by a tyrosine-containing motif (NPXY) in the cytoplasmic tail of the receptor (1Davis C.G. Lehrman M.A. Russell D.W. Anderson R.G. Brown M.S. Goldstein J.L. Cell. 1986; 45: 15-24Abstract Full Text PDF PubMed Scopus (242) Google Scholar). The molecular machinery that sorts the LDLR to coated pits and promotes its rapid internalization has not been fully defined. Recently a crucial component of the machinery that internalizes LDLR was identified by elucidation of the molecular basis of autosomal recessive hypercholesterolemia (ARH), a rare form of severe hypercholesterolemia. Patients with ARH have normal LDLR but markedly reduced clearance of circulating LDL by the liver (2Zuliani G. Vigna G.B. Corsini A. Maioli M. Romagnoni F. Fellin R. Eur. J. Clin. Investig. 1995; 25: 322-331Crossref PubMed Scopus (49) Google Scholar, 3Zuliani G. Arca M. Signore A. Bader G. Fazio S. Chianelli M. Bellosta S. Campagna F. Montali A. Maioli M. Pacifico A. Ricci G. Fellin R. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 802-809Crossref PubMed Scopus (86) Google Scholar). The disorder is caused by mutations that inactivate a 308-amino acid adaptor protein named ARH (4Garcia C.K. Wilund K. Arca M. Zuliani G. Fellin R. Maioli M. Calandra S. Bertolini S. Cossu F. Grishin N. Barnes R. Cohen J.C. Hobbs H.H. Science. 2001; 292: 1394-1398Crossref PubMed Scopus (478) Google Scholar). ARH contains four highly conserved domains (5Cohen J.C. Kimmel M. Polanski A. Hobbs H.H. Curr. Opin. Lipidol. 2003; 14: 121-127Crossref PubMed Scopus (51) Google Scholar, 6Soutar A.K. Naoumova R.P. Traub L.M. Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1963-1970Crossref PubMed Scopus (98) Google Scholar). The first is a ∼40-amino acid N-terminal domain of unknown function that is followed by a phosphotyrosine binding (PTB) domain (4Garcia C.K. Wilund K. Arca M. Zuliani G. Fellin R. Maioli M. Calandra S. Bertolini S. Cossu F. Grishin N. Barnes R. Cohen J.C. Hobbs H.H. Science. 2001; 292: 1394-1398Crossref PubMed Scopus (478) Google Scholar). PTB domains are found in a variety of adaptor proteins involved in receptor trafficking and signaling (7Yan K.S. Kuti M. Zhou M.M. FEBS Lett. 2002; 513: 67-70Crossref PubMed Scopus (60) Google Scholar). Typically PTB domains of adaptor proteins bind receptors via a consensus sequence, NPXY, in the cytoplasmic tail. In vitro studies with purified recombinant proteins indicate that the PTB domain of ARH binds to the unphosphorylated FDNPVY internalization sequence in LDLR in a sequence-specific manner (8Mishra S.K. Watkins S.C. Traub L.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16099-16104Crossref PubMed Scopus (148) Google Scholar, 9He G. Gupta S. Yi M. Michaely P. Hobbs H.H. Cohen J.C. J. Biol. Chem. 2002; 277: 44044-44049Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). PTB domains share structural similarity with phosphoinositide-binding pleckstrin homology domains (10Forman-Kay J.D. Pawson T. Curr. Opin. Struct. Biol. 1999; 9: 690-695Crossref PubMed Scopus (107) Google Scholar), and some PTB domains, including the domain in ARH, bind phosphoinositides (8Mishra S.K. Watkins S.C. Traub L.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16099-16104Crossref PubMed Scopus (148) Google Scholar, 11Howell B.W. Lanier L.M. Frank R. Gertler F.B. Cooper J.A. Mol. Cell. Biol. 1999; 19: 5179-5188Crossref PubMed Scopus (336) Google Scholar, 12Mishra S.K. Keyel P.A. Hawryluk M.J. Agostinelli N.R. Watkins S.C. Traub L.M. EMBO J. 2002; 21: 4915-4926Crossref PubMed Scopus (256) Google Scholar). Downstream of the PTB domain in ARH is a canonical clathrin box sequence (LLDLE), a conserved motif that mediates binding of several adaptor proteins to the terminal domain of the clathrin heavy chain (13Krupnick J.G. Goodman Jr., O.B. Keen J.H. Benovic J.L. J. Biol. Chem. 1997; 272: 15011-15016Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 14Traub L.M. J. Cell Biol. 2003; 163: 203-208Crossref PubMed Scopus (263) Google Scholar). The clathrin box sequence in ARH can mediate high affinity binding to the heavy chain of clathrin (8Mishra S.K. Watkins S.C. Traub L.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16099-16104Crossref PubMed Scopus (148) Google Scholar, 9He G. Gupta S. Yi M. Michaely P. Hobbs H.H. Cohen J.C. J. Biol. Chem. 2002; 277: 44044-44049Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Finally ARH contains a highly conserved sequence at its C terminus that binds the β2-subunit of AP2, a second structural protein in coated pits (9He G. Gupta S. Yi M. Michaely P. Hobbs H.H. Cohen J.C. J. Biol. Chem. 2002; 277: 44044-44049Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). The combination of these three functional regions in one protein coupled with the requirement of ARH for LDL endocytosis led to the proposition that ARH is required either to chaperone LDLR to the coated pit or to promote the internalization of the receptor (8Mishra S.K. Watkins S.C. Traub L.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16099-16104Crossref PubMed Scopus (148) Google Scholar, 9He G. Gupta S. Yi M. Michaely P. Hobbs H.H. Cohen J.C. J. Biol. Chem. 2002; 277: 44044-44049Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Elucidation of the specific role of ARH in LDLR endocytosis has been hampered by the fact that cultured skin fibroblasts, which provided critical insights into other aspects of LDLR function, do not recapitulate the defective LDLR internalization observed in ARH subjects (2Zuliani G. Vigna G.B. Corsini A. Maioli M. Romagnoni F. Fellin R. Eur. J. Clin. Investig. 1995; 25: 322-331Crossref PubMed Scopus (49) Google Scholar). Whereas fibroblasts from LDLR-/- patients (homozygous familial hypercholesterolemia) take up radiolabeled LDL at less than 10% of the rate observed in fibroblasts from normal fibroblasts from ARH subjects take up and LDL at of the normal rate M. Zuliani G. Wilund K. Campagna F. Fellin R. Bertolini S. Calandra S. Ricci G. N. Maioli M. P. Cossu F. Cohen J. Hobbs H.H. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In to fibroblasts, LDLR function is impaired in lymphocytes from ARH patients M. Naoumova R.P. A.K. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar). To further define the role of ARH in LDLR function we the distribution and binding of the LDLR in ARH-/- lymphocytes. cell were from used for and microscopy was from used in was a from The to LDL receptor was from receptor was from and was from and were from and and were from was from and and were from other were from LDL was from plasma J.L. S.K. Brown M.S. PubMed Scopus Google Scholar). Cell from circulating of normal subjects with ARH and subjects with familial were the J. Google Scholar). were in with and To of the LDLR, lymphocytes were in with 10% and and LDLR-/- lymphocytes were in for to on The were with and in in for at The were in and in in for in the cells were in for at and with in for with either receptor or were to the at The were with and for with and The were in to and a lymphocytes were in in for The lymphocytes were in and in were a with a The were in and and on at J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, Cell Biol. PubMed Scopus Google Scholar). the was at and the were The were by the on of the with the were on and in for at The were for in the of and in to a of The were on of and with in 10% normal Finally the with the were in with in for and with and J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). cell surface the lymphocytes were in and with in for The were by the cells for with in the cells were with and in the were in with and to the were with a a and on were with and were a electron at LDL was M. Brown M.S. Goldstein J.L. Anderson R.G. J. Cell Biol. PubMed Scopus Google Scholar). of 10% was to of of was and the was at for The was to to a of with and at for at to The was by at for at The was to a of The was and to an of LDL which had been in the to to the was on a and at for at The in the was in a in and of at The LDL was used of Immortalized lymphocytes were at in and cultured for were and at cells in of at either or to of LDL. The cells were at either or for to at for at and three C were and on of were by of cell and that had been with the and of cell with the The of the pit the of the coated and the number of with of these regions were The was the number of of the regions of the plasma membrane. of in the LDL were one since these of LDL. by a than were of Cell of lymphocytes were with C with and on a with to LDLR or a to the LDLR for at with were in C and in of C with of to for at with either or cells were three with C and with and in of protein was by the of M.M. PubMed Scopus Google Scholar), and the were of the The were to the In the of were to of were in used to cell surface LDLR was by the cell surface proteins M.J. J. 1995; PubMed Google Scholar). cells were with and in of for at with were with and with for on to were with and with of at for with were to at for in a to of of was of of was to of a of and of The was for at and The of which proteins The were three with and and in the that with the were and proteins on the cell was by the in at for were by to and for a of of the LDLR was a of the S.K. Goldstein J.L. Anderson R.G. Brown M.S. Cell. Full Text PDF PubMed Scopus Google Scholar). lymphocytes were into of was to a of for or that at the were into to further with in of and for at with were for surface of LDLR and β-migrating very low density lipoprotein binding assays were in J.L. S.K. Brown M.S. PubMed Scopus Google Scholar). and were at and at or with for with to of The used to the for the the In lymphocytes were in of The cells were with with increasing of LDL to The specific of the LDL in was the LDL and were by of the cells a of C 10% at for were in and to the and LDL. The of and LDL in was the specific of LDL in and into a assays were Goldstein J.L. Brown M.S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In normal LDL binds to the LDLR on the cell and the LDL·LDLR complex is and to In the low of the the receptor from the lipoprotein and to the cell LDL that is from the receptor in the endosome is to the The of is in ARH-/- lymphocytes an of LDL binding to the of these cells M. Naoumova R.P. A.K. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar). To the LDL in ARH-/- cells is due to a failure of LDLR ARH-/- and normal lymphocytes were with to LDLR and the of of LDLR from the cell surface were compared in the cell The of LDLR at the plasma was in normal lymphocytes, a similar to that in fibroblasts S.K. Goldstein J.L. Anderson R.G. Brown M.S. Cell. Full Text PDF PubMed Scopus Google Scholar). In of surface LDLR was in ARH-/- cells These are with a failure of LDLR to in ARH-/- lymphocytes. of the failure to internalize LDLR is an accumulation of receptors on the cell the of the LDLR in normal and ARH-/- cells In normal lymphocytes LDLR was observed predominantly in The LDLR with the early endosome and with the not In LDLR was predominantly on the cell surface of ARH-/- lymphocytes. The distribution of LDLR in the ARH-/- lymphocytes the distribution observed in from ARH-/- Cohen J.C. Hobbs H.H. J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of surface LDLR on normal and ARH-/- cells was by cell surface with and for the ARH-/- cells had more LDLR on the cell surface than normal cells similar increase in LDLR number was cell surface LDLRs were with or with followed by and of ARH the of LDLR on the cell In and ARH-/- cells were with a and with of of the was of the was with to in the portion of is an of and and were from LDLR-/- and were from normal and and were from ARH-/- cells. The portion of a quantification of the to In the number of LDLRs on the cell surface was by and normal lymphocytes with an the LDLR at for were and on a The protein was and used to In the number of LDLRs on the cell surface was by and ARH-/- lymphocytes and a with a the LDLR at were with and on a The protein was used to To the accumulation of LDLR on the plasma of ARH-/- lymphocytes a failure to the receptors in coated the surface distribution of LDLR was by In with the LDLR was located predominantly on the cell of ARH-/- lymphocytes, in normal cells the LDLR was with and of on the cell surface a increase in the number of of in the ARH-/- cells were at of in the coated pits of ARH-/- cells in normal cells The increase in the number of LDLRs in the pit of the ARH-/- cells in a in the of surface LDLRs in coated pits of the ARH-/- cells compared with normal cells the of ARH in a of LDLR from to the pit portion of the plasma the of LDLR in coated surface distribution of LDLR pit pit pit pit coated pit pit on the cell surface of and LDLR-/- cells were from and into either coated pit or pit the of an the and an of coated pit coated pit pit on the cell surface of and LDLR-/- cells were from and into either coated pit or pit the of an the and an of coated pits in a The increase in the number of cell surface LDLRs in ARH-/- lymphocytes observed in is higher than the increase in LDL binding observed M. Naoumova R.P. A.K. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar, M. M. P. Naoumova R.P. A.K. J. Clin. Investig. 2002; PubMed Scopus Google Scholar). we the of ARH-/- cells to bind LDLR which bind to LDLR and which binds to LDLR The surface binding of to ARH-/- cells was markedly than the binding of the normal cells which is with the increase in cell surface LDLR in the ARH-/- cells. binding was only 2-fold higher in ARH-/- cells than in the normal cells in with of the LDL binding of ARH-/- lymphocytes M. Naoumova R.P. A.K. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar, M. M. P. Naoumova R.P. A.K. J. Clin. Investig. 2002; PubMed Scopus Google Scholar). To the in LDL binding was due to a in the affinity of the LDLR for LDL in the ARH-/- we more binding indicated that the 2-fold increase in LDL binding to the ARH-/- cells was due to a increase in the number of high affinity LDL binding than to a increase in low affinity binding these binding indicated that the of LDLR on the cell surface of ARH-/- cells was to bind via To which LDLRs on the cell surface bind we the ARH-/- and normal cells with LDL for at either or and electron microscopy the ARH-/- cells more than normal which is with the binding assays and ARH-/- cells also had more than normal the increase was less than coated the number of of was to the number of of in normal and in ARH-/- cells and In binding to the surface of pit was less efficient in ARH-/- cells than in normal cells. in ARH-/- lymphocytes the LDLR binds LDL in coated pits but to bind LDL outside coated pits surface distribution of pit pit pit pit coated pit pit on the cell surface of and LDLR-/- cells were from and into either coated pit or pit the of an the and an of coated pit coated pit pit on the cell surface of and LDLR-/- cells were from and into either coated pit or pit the of an the and an of coated pits in a ARH promote LDL binding to the LDLR outside the coated is that the LDLR in ARH-/- cells a that with LDL binding. by the on of the LDLR from the ARH-/- and normal in were not from the cell in LDL binding the in LDL binding in ARH-/- cells not to to the LDLR but is specific to the of the we the of LDLRs on ARH-/- cells to bind LDL was due to the of LDLR and protein or J.D. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). were with or to to for LDL binding. in the LDL binding were in the ARH-/- cells these also not in the of LDLR from ARH-/- cells on we in of LDLRs C.G. Goldstein J.L. Brown M.S. J. Biol. Chem. Full Text PDF PubMed Google from the cell not the failure of LDLR to bind LDL not to due to of to the receptor The of indicate that the adaptor protein ARH a crucial role in binding and internalization of the of ARH in failure of LDLR endocytosis and a dramatic of LDLR that the of receptors were on the cell surface than in microscopy that of the LDLRs on the of ARH-/- cells were outside coated pits and were to bind LDL. Biochemical studies that a >20-fold increase in LDLR on the cell LDL cell surface binding was only in ARH-/- cells. coated ARH-/- cells had at LDLR and LDL binding normal cells. the LDLR and LDL were not from these pits. ARH was not required for of the LDLR to coated pits but to required for endocytosis of the LDLR from pits. In the failure of of LDLR in ARH-/- cells to bind LDL that ARH the of LDLR to bind LDL in have that ARH is required for normal and of LDL in lymphocytes and in liver Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar, Cohen J.C. Hobbs H.H. J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), but the specific role of ARH in endocytosis has not been defined. The that ARH can bind to LDLR, and that ARH the LDLR to the machinery and LDLR to coated pits or the receptor in the pit indicated that the number of LDLRs in coated pits was similar in normal and ARH-/- lymphocytes and that the number of LDL in coated pits was normal in ARH-/- cells. normal ARH-/- cells not in of and at were also to LDLR internalization in ARH-/- cells. the of LDLR and LDL in coated pits of ARH-/- was The failure to internalize LDLR is with the reduced and of observed in ARH-/- lymphocytes M. Naoumova R.P. A.K. J. Clin. Investig. 1999; PubMed Scopus Google Scholar, Yi M. Campagna F. Arca M. Zuliani G. Fellin R. Hobbs H.H. Cohen J.C. Mol. 2002; PubMed Scopus Google Scholar, M. M. P. Naoumova R.P. A.K. J. Clin. Investig. 2002; PubMed Scopus Google Scholar). These that the of ARH the LDLR trafficking at the of endocytosis of LDLR from coated pits. ARH involved in the endocytosis of LDLR from coated ARH the endocytosis of LDLR and from coated pits by the the receptor and the structural of the of receptors in coated pits can mediated by a in which of low but in to the rate of receptors from coated pits A. S. 2003; PubMed Scopus Google Scholar). In with coated pits binding for LDLR including S. T. 2002; PubMed Scopus Google Scholar), PTB adaptor proteins S.K. Keyel P.A. Hawryluk M.J. Agostinelli N.R. Watkins S.C. Traub L.M. EMBO J. 2002; 21: 4915-4926Crossref PubMed Scopus (256) Google Scholar, Cohen J.C. Hobbs H.H. J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google and the clathrin heavy chain R.G. J. L.M. Anderson R.G. J. Cell Biol. PubMed Scopus Google Scholar). The associations of these or ARH-/- cells to LDLR in coated pits but to the receptor in the invaginating portion of the budding In fibroblasts, LDLRs to from the invaginating portion of coated pits pit budding R.G. Brown M.S. Goldstein J.L. Cell. Full Text PDF PubMed Scopus Google Scholar), that receptors are not by the budding portion of the coated ARH the of the receptor with the invaginating portion of the budding pit, thereby increasing the efficiency of LDLR internalization. The second of is that the of ARH the of more than of cell surface LDLR to bind LDL. In coated the of LDL to LDLR was similar in normal and ARH-/- cells. of the of to in the pit of normal and ARH-/- cells indicated that the receptors that to bind LDL on ARH-/- cells were predominantly located outside coated pits. The of LDL to LDLR also indicated that in normal cells LDL to the LDLR with efficiency coated pits than efficiency can by receptor from binding of LDL to LDLR the receptors are at high density are in coated pits M.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In ARH-/- cells less efficient binding of LDL to receptors outside of coated pits than pits. These suggest that ARH a role in the LDL binding of receptors outside coated pits. is ARH in LDL binding by the of LDL binding to ARH-/- cells indicated that the of LDLR that to LDL with normal affinity The receptors from ARH-/- and normal cells not to have since the LDLR had on and of in associations of the LDLR with also not to the of the LDL binding since ARH-/- cells with or not to bind LDL also not in the of LDLR from ARH-/- cells on we in of LDLR C.G. Goldstein J.L. Brown M.S. J. Biol. Chem. Full Text PDF PubMed Google from the cell the failure of LDLRs in ARH-/- cells to bind LDL was not an of the LDLR were the LDLRs by an ARH LDL the In the of ARH, the LDLR located outside the pits with the cell surface in a manner that the binding domains are The binding on LDLR a surface G. K. K. Brown M.S. Goldstein J.L. J. Science. 2002; PubMed Scopus Google Scholar), and the first In the binding only Brown M.S. Goldstein J.L. Russell D.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.W. Brown M.S. Goldstein J.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar). to binding to but not binding. ARH binding to the cytoplasmic tail of LDLR, in combination with ARH binding to the the of the binding domains of LDLR and thereby to LDL. LDL is to bind to the LDLR in the coated pits of the ARH-deficient other LDLR binding can promote the of the binding The that ARH is required for binding and internalization of LDLR that ARH a more complex role in LDL than the of electron microscopy quantification in and also and for
Michaely et al. (Tue,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: