Distinct binding sites in the structure of alpha 2-macroglobulin mediate the interaction with beta-amyloid peptide and growth factors - PubMed (original) (raw)
. 2002 Apr 12;277(15):13338-45.
doi: 10.1074/jbc.M106792200. Epub 2002 Jan 31.
Affiliations
- PMID: 11823454
- DOI: 10.1074/jbc.M106792200
Free article
Distinct binding sites in the structure of alpha 2-macroglobulin mediate the interaction with beta-amyloid peptide and growth factors
Joseph M Mettenburg et al. J Biol Chem. 2002.
Free article
Abstract
Alpha(2)-macroglobulin (alpha(2)M) and its receptor, low density lipoprotein receptor-related protein (LRP), function together to facilitate the cellular uptake and degradation of beta-amyloid peptide (Abeta). In this study, we demonstrate that Abeta binds selectively to alpha(2)M that has been induced to undergo conformational change by reaction with methylamine. Denatured alpha(2)M subunits, which were immobilized on polyvinylidene difluoride membranes, bound Abeta, suggesting that alpha(2)M tertiary and quaternary structure are not necessary. To determine whether a specific sequence in alpha(2)M is responsible for Abeta binding, we prepared and analyzed defined alpha(2)M fragments and glutathione S-transferase-alpha(2)M peptide fusion proteins. A single sequence, centered at amino acids (aa) 1314-1365, was identified as the only major Abeta-binding site. Importantly, Abeta did not bind to the previously characterized growth factor-binding site (aa 718-734). Although the Abeta binding sequence is adjacent to the binding site for LRP, the results of experiments with mutated fusion proteins indicate that the two sites are distinct. Furthermore, a saturating concentration of Abeta did not inhibit LRP-mediated clearance of alpha(2)M-MA in mice. Using various methods, we determined that the K(D) for the interaction of Abeta with its binding site in the individual alpha(2)M subunit is 0.7-2.4 microm. The capacity of alpha(2)M to bind Abeta and deliver it to LRP may be greater than that predicted by the K(D), because each alpha(2)M subunit may bind Abeta and the bound Abeta may multimerize. These studies suggest a model in which alpha(2)M has three protein interaction sites with distinct specificities, mediating the interaction with Abeta, growth factors, and LRP.
Similar articles
- Recognition of alpha 2-macroglobulin by the low density lipoprotein receptor-related protein requires the cooperation of two ligand binding cluster regions.
Mikhailenko I, Battey FD, Migliorini M, Ruiz JF, Argraves K, Moayeri M, Strickland DK. Mikhailenko I, et al. J Biol Chem. 2001 Oct 19;276(42):39484-91. doi: 10.1074/jbc.M104382200. Epub 2001 Aug 15. J Biol Chem. 2001. PMID: 11507091 - Identification and characterization of the acidic pH binding sites for growth regulatory ligands of low density lipoprotein receptor-related protein-1.
Ling TY, Chen CL, Huang YH, Liu IH, Huang SS, Huang JS. Ling TY, et al. J Biol Chem. 2004 Sep 10;279(37):38736-48. doi: 10.1074/jbc.M310537200. Epub 2004 Jun 28. J Biol Chem. 2004. PMID: 15226301 - Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition.
Harris-White ME, Frautschy SA. Harris-White ME, et al. Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):469-80. doi: 10.2174/156800705774322102. Curr Drug Targets CNS Neurol Disord. 2005. PMID: 16266282 Review.
Cited by
- Extracellular protein homeostasis in neurodegenerative diseases.
Wilson MR, Satapathy S, Vendruscolo M. Wilson MR, et al. Nat Rev Neurol. 2023 Apr;19(4):235-245. doi: 10.1038/s41582-023-00786-2. Epub 2023 Feb 24. Nat Rev Neurol. 2023. PMID: 36828943 Review. - A2M is a potential core gene in intrahepatic cholangiocarcinoma.
Zhang G, Liu X, Sun Z, Feng X, Wang H, Hao J, Zhang X. Zhang G, et al. BMC Cancer. 2022 Jan 3;22(1):5. doi: 10.1186/s12885-021-09070-2. BMC Cancer. 2022. PMID: 34979994 Free PMC article. - Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.
Cater JH, Wilson MR, Wyatt AR. Cater JH, et al. Oxid Med Cell Longev. 2019 Jul 22;2019:5410657. doi: 10.1155/2019/5410657. eCollection 2019. Oxid Med Cell Longev. 2019. PMID: 31428227 Free PMC article. Review. - Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide.
Cater JH, Kumita JR, Zeineddine Abdallah R, Zhao G, Bernardo-Gancedo A, Henry A, Winata W, Chi M, Grenyer BSF, Townsend ML, Ranson M, Buhimschi CS, Charnock-Jones DS, Dobson CM, Wilson MR, Buhimschi IA, Wyatt AR. Cater JH, et al. Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6101-6110. doi: 10.1073/pnas.1817298116. Epub 2019 Mar 8. Proc Natl Acad Sci U S A. 2019. PMID: 30850528 Free PMC article. - Changes Due to Ageing in the Glycan Structure of Alpha-2-Macroglobulin and Its Reactivity with Ligands.
Šunderić M, Križáková M, Malenković V, Ćujić D, Katrlík J, Nedić O. Šunderić M, et al. Protein J. 2019 Feb;38(1):23-29. doi: 10.1007/s10930-018-9806-6. Protein J. 2019. PMID: 30564965
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous