| Structural highlights
Disease
[LDLR_HUMAN] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:143890]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [:][32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]
Function
[LDLR_HUMAN] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The low-density lipoprotein receptor (LDLR) is the primary mechanism for uptake of cholesterol-carrying particles into cells. The region of the LDLR implicated in receptor recycling and lipoprotein release at low pH contains a pair of calcium-binding EGF-like modules, followed by a series of six YWTD repeats and a third EGF-like module. The crystal structure at 1.5 A resolution of a receptor fragment spanning the YWTD repeats and its two flanking EGF modules reveals that the YWTD repeats form a six-bladed beta-propeller that packs tightly against the C-terminal EGF module, whereas the EGF module that precedes the propeller is disordered in the crystal. Numerous point mutations of the LDLR that result in the genetic disease familial hypercholesterolemia (FH) alter side chains that form conserved packing and hydrogen bonding interactions in the interior and between propeller blades. A second subset of FH mutations are located at the interface between the propeller and the C-terminal EGF module, suggesting a structural requirement for maintaining the integrity of the interdomain interface.
Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair.,Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC Nat Struct Biol. 2001 Jun;8(6):499-504. PMID:11373616[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Maruyama T, Miyake Y, Tajima S, Harada-Shiba M, Yamamura T, Tsushima M, Kishino B, Horiguchi Y, Funahashi T, Matsuzawa Y, et al.. Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1713-8. PMID:7583548
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- ↑ Ekstrom U, Abrahamson M, Sveger T, Lombardi P, Nilsson-Ehle P. An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia. Hum Genet. 1995 Aug;96(2):147-50. PMID:7635461
- ↑ Leren TP, Solberg K, Rodningen OK, Tonstad S, Ose L. Two novel point mutations in the EGF precursor homology domain of the LDL receptor gene causing familial hypercholesterolemia. Hum Genet. 1995 Aug;96(2):241-2. PMID:7635482
- ↑ Giesel J, Holzem G, Oette K. Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolemia. Hum Genet. 1995 Sep;96(3):301-4. PMID:7649546
- ↑ Pereira E, Ferreira R, Hermelin B, Thomas G, Bernard C, Bertrand V, Nassiff H, Mendez del Castillo D, Bereziat G, Benlian P. Recurrent and novel LDL receptor gene mutations causing heterozygous familial hypercholesterolemia in La Habana. Hum Genet. 1995 Sep;96(3):319-22. PMID:7649549
- ↑ Gundersen KE, Solberg K, Rodningen OK, Tonstad S, Ose L, Berg K, Leren TP. Two novel missense mutations in the LDL receptor gene causing familial hypercholesterolemia. Clin Genet. 1996 Feb;49(2):85-7. PMID:8740918
- ↑ Sundvold H, Solberg K, Tonstad S, Rodningen OK, Ose L, Berg K, Leren TP. A common missense mutation (C210G) in the LDL receptor gene among Norwegian familial hypercholesterolemia subjects. Hum Mutat. 1996;7(1):70-1. PMID:8664907 doi:<70::AID-HUMU12>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)7:1<70::AID-HUMU12>3.0.CO;2-P
- ↑ Webb JC, Sun XM, McCarthy SN, Neuwirth C, Thompson GR, Knight BL, Soutar AK. Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. J Lipid Res. 1996 Feb;37(2):368-81. PMID:9026534
- ↑ Peeters AV, Van Gaal LF, du Plessis L, Lombardi MP, Havekes LM, Kotze MJ. Mutational and genetic origin of LDL receptor gene mutations detected in both Belgian and Dutch familial hypercholesterolemics. Hum Genet. 1997 Aug;100(2):266-70. PMID:9254862
- ↑ Jensen HK, Jensen TG, Faergeman O, Jensen LG, Andresen BS, Corydon MJ, Andreasen PH, Hansen PS, Heath F, Bolund L, Gregersen N. Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia. Hum Mutat. 1997;9(5):437-44. PMID:9143924 doi:<437::AID-HUMU10>3.0.CO;2-3 10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3
- ↑ Day IN, Whittall RA, O'Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE. Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat. 1997;10(2):116-27. PMID:9259195 doi:<116::AID-HUMU4>3.0.CO;2-I 10.1002/(SICI)1098-1004(1997)10:2<116::AID-HUMU4>3.0.CO;2-I
- ↑ Leren TP, Tonstad S, Gundersen KE, Bakken KS, Rodningen OK, Sundvold H, Ose L, Berg K. Molecular genetics of familial hypercholesterolaemia in Norway. J Intern Med. 1997 Mar;241(3):185-94. PMID:9104431
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- ↑ Couture P, Vohl MC, Gagne C, Gaudet D, Torres AL, Lupien PJ, Despres JP, Labrie F, Simard J, Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians. Hum Mutat. 1998;Suppl 1:S226-31. PMID:9452094
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- ↑ Mak YT, Zhang J, Chan YS, Mak TW, Tomlinson B, Masarei JR, Pang CP. Possible common mutations in the low density lipoprotein receptor gene in Chinese. Hum Mutat. 1998;Suppl 1:S310-3. PMID:9452118
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- ↑ Motti C, Bertolini S, Rampa P, Trovatello G, Liberatoscioli L, Calandra S, Federici G, Cortese C. Two novel mutations consisting in minor gene rearrangements in the human low density lipoprotein receptor gene in Italian patients affected by familial hypercholesterolemia. Mutations in brief no. 194. Online. Hum Mutat. 1998;12(3):290. PMID:10660340
- ↑ Hirayama T, Yamaki E, Hata A, Tsuji M, Hashimoto K, Yamamoto M, Emi M. Five familial hypercholesterolemic kindreds in Japan with novel mutations of the LDL receptor gene. J Hum Genet. 1998;43(4):250-4. PMID:9852677 doi:10.1007/s100380050083
- ↑ Lee WK, Haddad L, Macleod MJ, Dorrance AM, Wilson DJ, Gaffney D, Dominiczak MH, Packard CJ, Day IN, Humphries SE, Dominiczak AF. Identification of a common low density lipoprotein receptor mutation (C163Y) in the west of Scotland. J Med Genet. 1998 Jul;35(7):573-8. PMID:9678702
- ↑ Ekstrom U, Abrahamson M, Floren CH, Tollig H, Wettrell G, Nilsson G, Sun XM, Soutar AK, Nilsson-Ehle P. An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F). Clin Genet. 1999 May;55(5):332-9. PMID:10422803
- ↑ Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, Stuhrmann M. Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online. Hum Mutat. 1999;13(3):257. PMID:10090484 doi:<257::AID-HUMU15>3.0.CO;2-A 10.1002/(SICI)1098-1004(1999)13:3<257::AID-HUMU15>3.0.CO;2-A
- ↑ Hattori H, Nagano M, Iwata F, Homma Y, Egashira T, Okada T. Identification of recurrent and novel mutations in the LDL receptor gene in Japanese familial hypercholesterolemia. Mutation in brief no. 248. Online. Hum Mutat. 1999;14(1):87. PMID:10447263 doi:<87::AID-HUMU14>3.0.CO;2-N 10.1002/(SICI)1098-1004(1999)14:1<87::AID-HUMU14>3.0.CO;2-N
- ↑ Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S. Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52. PMID:10978268
- ↑ Miltiadous G, Elisaf M, Xenophontos S, Manoli P, Cariolou MA. Segregation of a novel LDLR gene mutation (I430T) with familial hypercholesterolaemia in a Greek pedigree. Hum Mutat. 2000 Sep;16(3):277. PMID:10980548 doi:<277::AID-HUMU24>3.0.CO;2-Y 10.1002/1098-1004(200009)16:3<277::AID-HUMU24>3.0.CO;2-Y
- ↑ Thiart R, Scholtz CL, Vergotine J, Hoogendijk CF, de Villiers JN, Nissen H, Brusgaard K, Gaffney D, Hoffs MS, Vermaak WJ, Kotze MJ. Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia. J Med Genet. 2000 Jul;37(7):514-9. PMID:10882754
- ↑ Takahashi M, Ikeda U, Takahashi S, Hattori H, Iwasaki T, Ishihara M, Egashira T, Honma S, Asano Y, Shimada K. A novel mutation in exon 2 of the low-density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia. Clin Genet. 2001 Apr;59(4):290-2. PMID:11298688
- ↑ Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006 Dec;43(12):943-9. PMID:17142622 doi:10.1136/jmg.2006.038356
- ↑ Abifadel M, Rabes JP, Jambart S, Halaby G, Gannage-Yared MH, Sarkis A, Beaino G, Varret M, Salem N, Corbani S, Aydenian H, Junien C, Munnich A, Boileau C. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat. 2009 Jul;30(7):E682-91. doi: 10.1002/humu.21002. PMID:19319977 doi:10.1002/humu.21002
- ↑ Walus-Miarka M, Sanak M, Idzior-Walus B, Miarka P, Witek P, Malecki MT, Czarnecka D. A novel mutation (Cys308Phe) of the LDL receptor gene in families from the South-Eastern part of Poland. Mol Biol Rep. 2012 May;39(5):5181-6. doi: 10.1007/s11033-011-1314-0. Epub 2011, Dec 13. PMID:22160468 doi:10.1007/s11033-011-1314-0
- ↑ Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol. 2001 Jun;8(6):499-504. PMID:11373616 doi:10.1038/88556
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