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Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms
Biochemie-Zentrum der Universität Heidelberg, INF 328, D-69120 Heidelberg, Germany
Received: 11 January 2009; Accepted: 23 February 2009 / Published: 2 March 2009
Abstract: The closely related human and murine proteins Hap46/BAG-1M and BAG-1, respectively, were discovered more than a decade ago by molecular cloning techniques. These and the larger isoform Hap50/BAG-1L, as well as shorter isoforms, have the ability to interact with a seemingly unlimited array of proteins of completely unrelated structures. This problem was partially resolved when it was realized that molecular chaperones of the hsp70 heat shock protein family are major primary association partners, binding being mediated by the carboxy terminal BAG-domain and the ATP-binding domain of hsp70 chaperones. The latter, in turn, can associate with an almost unlimited variety of proteins through their substrate-binding domains, so that ternary complexes may result. The protein folding activity of hsp70 chaperones is affected by interactions with Hap46/BAG-1M or isoforms. However, there also exist several proteins which bind to Hap46/BAG-1M and isoforms independent of hsp70 mediation. Moreover, Hap46/BAG-1M and Hap50/BAG-1L, but not the shorter isoforms, can bind to DNA in a sequence-independent manner by making use of positively charged regions close to their amino terminal ends. This is the molecular basis for their effects on transcription which are of major physiological relevance, as discussed here in terms of a model. The related proteins Hap50/BAG-1L and Hap46/BAG-1M may thus serve as molecular links between such diverse bioactivities as regulation of gene expression and protein quality control. These activities are coordinated and synergize in helping cells to cope with conditions of external stress. Moreover, they recently became markers for the aggressiveness of several cancer types.
Keywords: Apoptosis; DNA binding; hsp70 molecular chaperones; multifunctional proteins; protein folding; transcriptional regulation
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Gehring, U. Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms. Int. J. Mol. Sci. 2009, 10, 906-928.
Gehring U. Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms. International Journal of Molecular Sciences. 2009; 10(3):906-928.
Gehring, Ulrich. 2009. "Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms." Int. J. Mol. Sci. 10, no. 3: 906-928.