Homo- and Heterodimerization of APP Family Members Promotes Intercellular Adhesion

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Sep 30

PMID 16193067

Citations 144

Authors

Peter Soba

Simone Eggert

Katja Wagner

Hanswalter Zentgraf

Katjuscha Siehl

Sylvia Kreger

Alexander Lower

Andreas Langer

Gunter Merdes

Renato Paro

Colin L Masters

Ulrike Muller

Stefan Kins

Konrad Beyreuther

Affiliations

Soon will be listed here.

Abstract

The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its physiological function and that of its mammalian paralogs, the amyloid precursor-like proteins 1 and 2 (APLPs), is still poorly understood. APP has been proposed to form dimers, a process that could promote cell adhesion via trans-dimerization. We investigated the dimerization and cell adhesion properties of APP/APLPs and provide evidence that all three paralogs are capable of forming homo- and heterocomplexes. Moreover, we show that trans-interaction of APP family proteins promotes cell-cell adhesion in a homo- and heterotypic fashion and that endogenous APLP2 is required for cell-cell adhesion in mouse embryonic fibroblasts. We further demonstrate interaction of all the three APP family members in mouse brain, genetic interdependence, and molecular interaction of APP and APLPs in synaptically enriched membrane compartments. Together, our results provide evidence that homo- and heterocomplexes of APP/APLPs promote trans-cellular adhesion in vivo.

Citing Articles

The AICD interactome: implications in neurodevelopment and neurodegeneration.

Ng L, Chow J, Lau K Biochem Soc Trans. 2024; 52(6):2539-2556.

PMID: 39670668 PMC: 11668293. DOI: 10.1042/BST20241510.

Zinc and copper effect mechanical cell adhesion properties of the amyloid precursor protein.

August A, Hartmann S, Schilling S, Muller-Renno C, Begic T, Pierik A Biol Chem. 2024; 405(11-12):701-710.

PMID: 39425975 DOI: 10.1515/hsz-2024-0054.

CNTN4 modulates neural elongation through interplay with APP.

Bamford R, Zuko A, Eve M, Sprengers J, Post H, Taggenbrock R Open Biol. 2024; 14(5):240018.

PMID: 38745463 PMC: 11293442. DOI: 10.1098/rsob.240018.

Genome-wide epistasis analysis reveals gene-gene interaction network on an intermediate endophenotype P-tau/Aβ ratio in ADNI cohort.

Zhang Q, Liu J, Liu H, Ao L, Xi Y, Chen D Sci Rep. 2024; 14(1):3984.

PMID: 38368488 PMC: 10874417. DOI: 10.1038/s41598-024-54541-8.

Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging.

Nithianandam V, Bukhari H, Leventhal M, Battaglia R, Dong X, Fraenkel E Nat Commun. 2023; 14(1):7034.

PMID: 37923712 PMC: 10624868. DOI: 10.1038/s41467-023-42822-1.

References

Islam R, Kristiansen L, Romani S, Garcia-Alonso L, Hortsch M . Activation of EGF receptor kinase by L1-mediated homophilic cell interactions. Mol Biol Cell. 2004; 15(4):2003-12. PMC: 379294. DOI: 10.1091/mbc.e03-05-0333. View

Takai Y, Shimizu K, Ohtsuka T . The roles of cadherins and nectins in interneuronal synapse formation. Curr Opin Neurobiol. 2003; 13(5):520-6. DOI: 10.1016/j.conb.2003.09.003. View

Eggert S, Paliga K, Soba P, Evin G, Masters C, Weidemann A . The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. J Biol Chem. 2004; 279(18):18146-56. DOI: 10.1074/jbc.M311601200. View

Wang Y, Ha Y . The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell. 2004; 15(3):343-53. DOI: 10.1016/j.molcel.2004.06.037. View

Merdes G, Soba P, Loewer A, Bilic M, Beyreuther K, Paro R . Interference of human and Drosophila APP and APP-like proteins with PNS development in Drosophila. EMBO J. 2004; 23(20):4082-95. PMC: 524346. DOI: 10.1038/sj.emboj.7600413. View

Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H . Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 2004; 23(20):4106-15. PMC: 524337. DOI: 10.1038/sj.emboj.7600390. View

Tanzi R, McClatchey A, Lamperti E, Gusella J, Neve R . Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 1988; 331(6156):528-30. DOI: 10.1038/331528a0. View

Weidemann A, Konig G, Bunke D, Fischer P, Salbaum J, Masters C . Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989; 57(1):115-26. DOI: 10.1016/0092-8674(89)90177-3. View

Miura M, Asou H, Kobayashi M, Uyemura K . Functional expression of a full-length cDNA coding for rat neural cell adhesion molecule L1 mediates homophilic intercellular adhesion and migration of cerebellar neurons. J Biol Chem. 1992; 267(15):10752-8. View

10.

Small D, Nurcombe V, Moir R, Michaelson S, Monard D, Beyreuther K . Association and release of the amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix. J Neurosci. 1992; 12(11):4143-50. PMC: 6576018. View

11.

Ferreira A, Caceres A, Kosik K . Intraneuronal compartments of the amyloid precursor protein. J Neurosci. 1993; 13(7):3112-23. PMC: 6576677. View

12.

Slunt H, Thinakaran G, von Koch C, Lo A, Tanzi R, Sisodia S . Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem. 1994; 269(4):2637-44. View

13.

Moya K, Benowitz L, Schneider G, Allinquant B . The amyloid precursor protein is developmentally regulated and correlated with synaptogenesis. Dev Biol. 1994; 161(2):597-603. DOI: 10.1006/dbio.1994.1055. View

14.

Yamazaki T, Selkoe D, Koo E . Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J Cell Biol. 1995; 129(2):431-42. PMC: 2199904. DOI: 10.1083/jcb.129.2.431. View

15.

Zheng H, Jiang M, Trumbauer M, Sirinathsinghji D, Hopkins R, Smith D . beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995; 81(4):525-31. DOI: 10.1016/0092-8674(95)90073-x. View

16.

Lorent K, Overbergh L, Moechars D, De Strooper B, Van Leuven F, Van Den Berghe H . Expression in mouse embryos and in adult mouse brain of three members of the amyloid precursor protein family, of the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein and of its ligands apolipoprotein E, lipoprotein.... Neuroscience. 1995; 65(4):1009-25. DOI: 10.1016/0306-4522(94)00555-j. View

17.

Kim T, Wu K, Xu J, McAuliffe G, Tanzi R, Wasco W . Selective localization of amyloid precursor-like protein 1 in the cerebral cortex postsynaptic density. Brain Res Mol Brain Res. 1995; 32(1):36-44. DOI: 10.1016/0169-328x(95)00328-p. View

18.

Beher D, Hesse L, Masters C, Multhaup G . Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I. J Biol Chem. 1996; 271(3):1613-20. DOI: 10.1074/jbc.271.3.1613. View

19.

Li Z, Stark G, Gotz J, Rulicke T, Gschwind M, Huber G . Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells. Proc Natl Acad Sci U S A. 1996; 93(12):6158-62. PMC: 39206. DOI: 10.1073/pnas.93.12.6158. View

20.

Sandbrink R, Monning U, Masters C, Beyreuther K . Expression of the APP gene family in brain cells, brain development and aging. Gerontology. 1997; 43(1-2):119-31. DOI: 10.1159/000213840. View