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Human Molecular Genetics, 2002, Vol. 11, No. 9 1037-1044
© 2002 Oxford University Press

Identification of a novel family of presenilin homologues

Chris P. Ponting1,*, Mike Hutton2, Andrew Nyborg2, Matthew Baker2, Karen Jansen2 and Todd E. Golde2

1MRC Functional Genetics Unit, University of Oxford, Department of Human Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK and 2Mayo Clinic Jacksonville, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Presenilins have been shown to influence limited proteolysis of amyloid ß protein precursor (APP), Notch and ErbB4, and have been proposed to be {gamma}-secretases that perform the terminal cleavage of APP. In this model, two conserved and apparently intramembranous aspartic acids participate in catalysis. Highly sequence-similar presenilin homologues are known in plants, invertebrates and vertebrates. In this work, we have used a combination of different sequence database search methods to identify a new family of proteins homologous to presenilins. Members of this family, which we term presenilin homologues (PSH), have significant sequence similarities to presenilins and also possess two conserved aspartic acid residues within adjacent predicted transmembrane segments. The PSH family is found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five PSHs are detectable in the human genome, of which three possess ‘protease-associated’ domains that are consistent with the proposed protease function of PSs. Based on these findings, we propose that PSs and PSHs represent different sub-branches of a larger family of polytopic membrane-associated aspartyl proteases.

* To whom correspondence should be addressed: Tel: +44 1865 272175; Fax: +44 1865 282651; Email: Chris.Ponting{at}anat.ox.ac.uk


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