Membrane topology of gp41 and amyloid precursor protein: interfering transmembrane interactions as potential targets for HIV and Alzheimer treatment.
The amyloid precursor protein (APP), that plays a critical role in the development of senile plaques in Alzheimer disease (AD), and the gp41 envelope protein of the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), are single-spanning type-1 transmembrane (TM) glycoproteins with the ability to form homo-oligomers. In this review we describe similarities, both in structural terms and sequence determinants of their TM and juxtamembrane regions. The TM domains are essential not only for anchoring the proteins in membranes but also have functional roles. Both TM segments contain GxxxG motifs that drive TM associations within the lipid bilayer. They also each possess similar sequence motifs, positioned at the membrane interface preceding their TM domains. These domains are known as cholesterol recognition/interaction amino acid consensus (CRAC) motif in gp41 and CRAC-like motif in APP. Moreover, in the cytoplasmic domain of both proteins other alpha-helical membranotropic regions with functional implications have been identified. Recent drug developments targeting both diseases are reviewed and the potential use of TM interaction modulators as therapeutic targets is discussed.
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Departament de Bioquímica i Biologia Molecular, Universitat de València. Dr. Moliner, 50, E-46100 Burjassot, Spain.
Martínez-Gil
Luis
L
Tamborero
Silvia
S
Mingarro
Ismael
I
D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism* / Q000628:therapy; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D015700:HIV Envelope Protein gp41