preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints202309.1250.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 13 September 2023 / Approved: 15 September 2023 / Online: 19 September 2023 (11:22:42 CEST)

Intrinsic disorder accounts for the flexibility of protein loops, molecular building blocks that are largely responsible for the processes and molecular functions of the living world. While loops likely represent early structural forms that served as intermediates in the emergence of protein structural domains, their origin and evolution remains poorly understood. Here, we conduct a phylogenomic survey of disorder in loop prototypes sourced from the ArchDB classification. Tracing prototypes associated with protein fold families along an evolutionary chronology revealed ancient prototypes tended to be more disordered than their derived counterparts, with ordered prototypes developing later in evolution. This highlights the central evolutionary role of disorder and flexibility. While mean disorder increased with time, a minority of ordered prototypes exist that emerged early in evolutionary history, possibly driven by the need to preserve specific molecular functions. We also revealed percolation of evolutionary constraints from higher to lower levels of organization. Percolation resulted in trade-offs between flexibility and rigidity that impacted prototype structure and geometry. Our findings provide a deep evolutionary view of the link between structure, disorder, flexibility and function, as well as insights into the evolutionary role of intrinsic disorder in loops and their contribution to protein structure and function.

chronology; early evolution; flexibility; intrinsically disordered region; loop prototype; molecular function; protein evolution; protein structure; structural domain

Biology and Life Sciences, Biochemistry and Molecular Biology

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