title: Coupling de novo protein folding with subunit exchange into pre-formed oligomeric protein complexes: the 'heritable template' hypothesis.
abstract: Despite remarkable advances in synthetic biology, the fact remains that it takes a living cell to make a new living cell. The information encoded in the genome is necessary to direct assembly of all cellular components, but it may not be sufficient. Some components (e.g. mitochondria) cannot be synthesized de novo, and instead require pre-existing templates, creating a fundamental continuity of life: if the template information is ever lost, the genomic code cannot suffice to ensure proper biogenesis. One type of information only incompletely encoded in the genome is the structures of macromolecular assemblies, which emerge from the conformations of the constituent molecules coupled with the ways in which these molecules interact. For many, if not most proteins, gene sequence is not the sole determinant of native conformation, particularly in the crowded cellular milieu. A partial solution to this problem lies in the functions of molecular chaperones, encoded by nearly all cellular genomes. Chaperones effectively restrict the ensemble of conformations sampled by polypeptides, promoting the acquisition of native, functional forms, but multiple proteins have evolved ways to achieve chaperone independence, perhaps by coupling folding with higher-order assembly. Here, I propose the existence of another solution: a novel mechanism of de novo folding in which the folding of specific proteins is templated by pre-folded molecules of a partner protein whose own folding also required similar templating. This hypothesis challenges prevailing paradigms by predicting that, in order to achieve a functional fold, some non-prion proteins require a seed passed down through generations.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McMurray
mesh_terms: D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D021122:Protein Subunits; D011506:Proteins