Novel Class of Polytopic Proteins with Domains Associated with Putative Protease Activity

A. P. Grigorenko^1,2, Y. K. Moliaka¹, G. I. Korovaitseva¹, and E. I. Rogaev^1*

¹Research Center of Mental Health, Russian Academy of Medical Sciences, Zagorodnoe Shosse 2/2, Moscow, 113152 Russia; fax: (095) 952-8940; E-mail: rogaev@dol.ru or Evgeny.Rogaev@umassmed.edu

²Institute of Molecular Genetics, Russian Academy of Sciences, pl. Kurchatova 46, Moscow, 123182 Russia; fax: (095) 196-0221

^* To whom correspondence should be addressed.

Received April 11, 2002; Revision received May 6, 2002

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A significant proportion of early onset Alzheimer's disease (AD) is caused by mutations in human genes for amyloid precursor protein (APP), presenilins 1 and 2 (PSEN1,2). AD associated mutations in PSEN1,2 genes alter the gamma-secretase cleavage activity of APP resulting in increased production of amyloidogenic Abeta42. PSEN dependent intramembrane proteolysis was described as an important step required for cleavage of Notch receptors, Notch-dependent signal transduction, and processing of other proteins. It is still unclear whether presenilins are unusual intramembrane proteases or they are necessary cofactors of gamma-secretase cleavage of APP and Notch. Identification of other proteins similar to presenilins may resolve this dilemma. We describe here the identification of novel families of genes encoding polytopic transmembrane proteins of Eukaryotes (IMPASes) and Arachaea(membrases). These proteins have a predicted structure similar to presenilins. The amino acid similarity is significant in domains carrying invariant amino acid residues, which are critical in specific presenilin-regulated endoproteolysis. Many members of the IMPAS family have protease associated domains (PA) typical of proteases. We identified and cloned five human IMPAS genes. Expression analysis of the hIMP1 gene (located on chromosome 20) was performed in human cell tissues and transfected cell cultures. The data demonstrate that a conservative class of putative protease-related polytopic proteins related to presenilins exists in multicellular eukaryotes and microorganisms.

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KEY WORDS: Alzheimer's disease, presenilins, APP, Notch, intramembrane proteolysis, gamma-secretase, aspartate, transmembrane domain, PA domain

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