Abstract
The amyloid precursor protein (APP) and its processing are widely believed to be central for the etiology of Alzheimer’s disease (AD) and appear essential for neuronal development and cell homeostasis in mammals. Many studies show the proteolysis of APP by the proteases α-, β- and γ-secretase, functional aspects of the protein and the structure of individual domains. It is, however, largely unclear and currently also widely debated of how the structures of individual domains and their interactions determine the observed functionalities of APP and how they are arranged within the three-dimensional architecture of the entire protein. Further unanswered questions relate to the physiologic function of APP, the regulation of its proteolytic processing and the structural and functional effect of its cellular trafficking and processing. In this review, we summarize our current understanding of the structure-function-relationship of the multi-domain protein APP. This type-I transmembrane protein consists of the two folded E1 and E2 segments that are connected to one another and to the single transmembrane helix by flexible segments and likely fulfills several independent functions.
About the authors
Ina Coburger studied biochemistry at the Friedrich-Schiller-University in Jena, Germany and obtained her diploma in 2010. Since then she has worked on her PhD in the laboratory of Manuel E. Than at the Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI). Her thesis is focused on structure-function relationships of APP.
Sandra Hoefgen studied biology at the Friedrich-Schiller-University in Jena, Germany and obtained her diploma in 2009. Since then she has worked on her PhD in the laboratory of Manuel E. Than at the Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI). Her thesis is focused on the dimerization behavior of APP.
Manuel E. Than is currently independent junior group leader and head of the protein crystallography group at the Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena, Germany. He studied Chemistry and Biochemistry in Bayreuth, Germany and Delaware, USA. In 2000 he received his PhD from the TU Munich, Germany, for structural biology work in the department of Robert Huber at the Max-Planck-Institute of Biochemistry on transmembrane and soluble proteins of the energy metabolism. During his postdoctoral time with Wolfram Bode and his habilitation at the Gene Center of the Ludwig Maximilians University Munich he predominantly worked on the structural biology of proteases and methodological developments in protein crystallography. His group that he founded in 2006 focuses on X-ray crystallographic, biochemical and biophysical investigations of proteins involved in the development of Alzheimer’s disease and other aging-related processes.
Acknowledgments
The work of M. E. Than was supported by a grant from the Deutsche Forschungsgemeinschaft (SFBs 596/604) and the work of S. Hoefgen from the Graduate School “Leibniz Graduate School on Ageing and Age-Related Diseases, LGSA” of the FLI. The authors apologize for the many interesting publications that could not be cited in this review because of space restrictions.
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