UCSF

Proteins are the molecular machines that perform the work of the cell. If DNA is the blueprint of life, proteins are the functional forms encoded by that instruction. Proteins are born through the process of protein translation, in which a given sequence of nucleotides is decoded into a corresponding chain of amino acids by the protein factory that is the ribosome. These chains of amino acids fold into sequence-specific structures capable of a diverse range of functions including chemical catalysis, membrane transport, force generation, and many more. As DNA inevitably mutates over time, the protein it encodes can concurrently drift in amino acid sequence and chemical properties. This presents opportunities for a cell to adapt to its environment by rewiring its protein machinery, but also challenges in accommodating potentially toxic loss-of-function changes. Herein is a collection of research investigating both how protein networks can be rewired through evolution and how the cell executes quality control of protein production – two different, yet intimately linked, nodes of cellular adaptation and survival. In the first chapter I discuss how protein kinases have an inherent plasticity that allows them to traverse broadened specificity intermediates throughout evolution, allowing for repeated sampling of new network connections. In the following chapter, I discuss how intrinsic protein-protein cooperativity can drive the development of similar DNA binding sites in multiple different biological lineages (an example of convergent evolution). In the final three chapters, I discuss how the Ribosome-associated Quality Control (RQC) complex combats proteostasis insult at the earliest stage of intervention – protein translation. The RQC engages incompletely synthesized proteins that have stalled within the ribosome, elongating and targeting them for degradation to prevent their potentially toxic accumulation. RQC failure has ramifications for protein homeostasis in general, but the integrity of this process is particularly important in long-lived, terminally differentiated cells like neurons and RQC defects are associated with neurodegenerative disease. Notably, RQC-driven protein elongation (or “CAT tailing”) occurs in a non-templated manner, involving only the ancient core of the ribosome and one RQC component with no role for mRNA or other canonical protein translation factors. The RQC component responsible for this peculiar activity appears to be conserved across all branches of life. In the concluding section, I discuss how the emergence of this non-templated peptide synthesis activity may have coincided with – or even predated – the evolution of canonical peptide synthesis, thereby potentiating the exploration of diverse protein sequence space before the fixation of a nucleotide code. The subsequent development of programmed protein synthesis led to the emergence of the innumerably complex biological forms and functions we see today.