Keeping harmful protein fibres at bay

Misfolded proteins are not just useless — they can be toxic. Some of them form linear aggregates known as amyloid fibres that can lead to disorders such as Alzheimer’s and Parkinson’s diseases. Writing in PLoS Biology, James Shorter and colleagues describe a protein machinery that inhibits the formation and helps to dissolve such fibres.

Heat shock proteins (HSPs) assist other proteins in folding. The authors set out to study whether two small HSPs from baker’s yeast (Hsp26 and Hsp42) could affect the generation of amyloid fibres by a misfolded protein of the same organism (Sup35). Using purified proteins, the researchers showed that Hsp26 and Hsp42 inhibited amyloid formation. Moreover, they determined exactly which steps of the process were affected: Hsp42 slowed down an early structural reorganization of small aggregates before the fibres were formed, whereas Hsp26 inhibited fibre growth.

Yeast cells have a protein called Hsp104 that rapidly dissolves amyloid. However, humans and other animals lack such an enzyme, and so it was unclear how our cells can get rid of amyloid fibres. The authors report that Sup35 fibres can be dissolved by a combination of several yeast HSPs (Hsp40, Hsp70 and Hsp110) in the absence of Hsp104, especially if the fibres are pretreated with Hsp26 and Hsp42. What’s more, they obtained similar results when using the equivalent human HSPs to disaggregate α-synuclein amyloid fibres, which are involved in Parkinson's disease. Although amyloid disassembly took many days, the researchers propose that such system could be functional in long-lasting cells such as neurons.

Shorter and colleagues’ findings suggest that enhancing the activity of certain HSPs in affected cells — and/or introducing yeast Hsp104 — could help to dissolve the amyloid in disorders such as Parkinson’s disease. However, additional research would be needed to assess the efficacy and safety of such potential treatments before these could be tested in people.

Reference (and source of the image):

Duennwald ML, Echeverria A, Shorter J (2012). Small Heat Shock Proteins Potentiate Amyloid Dissolution by Protein Disaggregases from Yeast and Humans. PLoS Biol, 10(6): e1001346. DOI: 10.1371/journal.pbio.1001346

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A new way to make polyketides

Polyketides are a class of natural products isolated from microbes, plants and invertebrates which includes an impressive number of clinically effective drugs with diverse activities. To name a few examples: erythromycin (antibiotic), rapamycin (immunosuppressive), amphotericin (antifungal), avermectin (antiparasitic), and doxorubicin (anticancer). As other natural products do, polyketides may play disparate roles in the producing organisms, from defensive weapons (inhibiting growth of competitors, or acting against predators) to signaling molecules (working as messengers between social organisms). In Mycobacterium tuberculosis, some polyketides are key intermediates in the synthesis of complex lipids. These lipids are important components of the unusually thick cell envelope, and help the microbe to be a successful pathogen. Therefore, the study of polyketide synthesis in this bacterium may lead to the design of specific inhibitors as new anti-mycobacterial drugs.

Polyketides are produced through a stepwise condensation of simple carboxylic acid precursors, resembling fatty acid biosythesis. This task is performed by enzymes known as polyketide synthases (PKSs). There are several types of PKSs, from relatively simple proteins to large multienzymatic complexes possessing tens of catalytic sites. They use any of two general mechanisms: (1) modular — in which each set of catalytic sites is used only once during the biosynthetic process, and (2) iterative — in which the same set of active sites is used repeatedly. This week in PLoS Biology, Rajesh Gokhale and colleagues present their research involving a peculiar PKS from M. tuberculosis. The PKS12 protein is encoded by the largest gene in the microbe's genome, and participates in the synthesis of an antigenic phosphoglycolipid. Most remarkably, this PKS appears to use a new hybrid "modularly iterative" mechanism for polyketide synthesis. Several molecules of the PKS12 protein join together to form a supramolecular assembly, which performs repetitive cycles of iterations. The protein assembly is formed by specific intermolecular interactions between N- and C-terminus linkers. This study provides another example of the catalytic and mechanistic versatility of PKSs — natural product biosynthesis is an inexhaustible source for new biochemistry!

Citation (open access):
Chopra T, Banerjee S, Gupta S, Yadav G, Anand S, Surolia A, Roy RP, Mohanty D, Gokhale RS (2008). Novel intermolecular iterative mechanism for biosynthesis of mycoketide catalyzed by a bimodular polyketide synthase. PLoS Biology 6(7), e163. DOI: 10.1371/journal.pbio.0060163

Image: model of the PKS12 protein, modified from Figure 5 of the cited article.


Related links:

• Cracking the Polyketide Code. PLoS Biology (2004) 2(2): e35.
• Polyketide Biosynthesis: The Erythromycin Example (video of an excellent talk by Chaitan Khosla, May 2007). iBioSeminars, American Society for Cell Biology. The first part of the talk (Polyketides and Polyketide Biosynthesis) is also available at Google Video, and is embedded below.

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