Review Structure and Function of the Molecular Chaperone Hsp104 from Yeast Valerie Grimminger-Marquardt, Hilal A. Lashuel Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne (EPFL), FSV-BMI AI 2137.1, Station 15, CH-1015 Lausanne, Switzerland Received 28 August 2009; accepted 1 September 2009 Published online 18 September 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/bip.21301 This article was originally published online as an accepted preprint. The ‘‘Published Online’’date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com INTRODUCTION S everal human diseases are caused by protein misfold- ing and the accumulation of toxic protein aggregates in the cytoplasm or extracellular space; these diseases include Alzheimer’s and Parkinson’s diseases, type II diabetes and the spongiform encephalopathies such as Creutzfeldt-Jakob disease. Therefore, understanding the molecular mechanisms involved in triggering and/or revers- ing protein aggregation in vivo is essential for elucidating the relationship between protein aggregation and disease and for developing effective therapeutic strategies to prevent, slow- down, or reverse the progression of these diseases. Several molecular chaperons have been shown to act individually or in concert with other chaperones to prevent protein misfold- Review Structure and Function of the Molecular Chaperone Hsp104 from Yeast Correspondence to: Hilal A. Lashuel; e-mail: hilal.lashuel@epfl.ch ABSTRACT: The molecular chaperone Hsp104 plays a central role in the clearance of aggregates after heat shock and the propagation of yeast prions. Hsp104’s disaggregation activity and prion propagation have been linked to its ability to resolubilize or remodel protein aggregates. However, Hsp104 has also the capacity to catalyze protein aggregation of some substrates at specific conditions. Hence, it is a molecular chaperone with two opposing activities with respect to protein aggregation. In yeast models of Huntington’s disease, Hsp104 is required for the aggregation and toxicity of polyglutamine (polyQ), but the expression of Hsp104 in cellular and animal models of Huntington’s and Parkinson’s disease protects against polyQ and a-synuclein toxicity. Therefore, elucidating the molecular determinants and mechanisms underlying the ability of Hsp104 to switch between these two activities is of critical importance for understanding its function and could provide insight into novel strategies aimed at preventing or reversing the formation of toxic protein aggregation in systemic and neurodegenerative protein misfolding diseases. Here, we present an overview of the current molecular models and hypotheses that have been proposed to explain the role of Hsp104 in modulating protein aggregation and prion propagation. The experimental approaches and the evidences presented so far in relation to these models are examined. Our primary objective is to offer a critical review that will inspire the use of novel techniques and the design of new experiments to proceed towards a qualitative and quantitative understanding of the molecular mechanisms underlying the multifunctional properties of Hsp104 in vivo. # 2009 Wiley Periodicals, Inc. Biopolymers 93: 252–276, 2010. Keywords: Hsp104; ClpB; Hsp100; AAA 1 -ATPase; disaggregation; molecular chaperones; neurodegenerative diseases; yeast prions; amyloid proteins; fibril formation; protein unfolding by chaperones Contract grant sponsors: Swiss Federal Institute of Technology Lausanne (HAL), Swiss National Science Foundation (HAL, 310000-110027), and Inter-European FP7 Marie Curie fellowship (VGM) V V C 2009 Wiley Periodicals, Inc. 252 Biopolymers Volume 93 / Number 3