High-throughput discovery of functional disordered regions: investigation of transactivation domains.

Molecular Systems Biology
Charles Nj RavaraniM Madan Babu

Abstract

Over 40% of proteins in any eukaryotic genome encode intrinsically disordered regions (IDRs) that do not adopt defined tertiary structures. Certain IDRs perform critical functions, but discovering them is non-trivial as the biological context determines their function. We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality-conferring patterns in their protein sequence are inferred through statistical learning. Using yeast HSF1 transcription factor-based assay, we discovered IDRs that function as transactivation domains (TADs) by screening a random sequence library and a designed library consisting of variants of 13 diverse TADs. Using machine learning, we find that segments devoid of positively charged residues but with redundant short sequence patterns of negatively charged and aromatic residues are a generic feature for TAD functionality. We anticipate that investigating defined sequence libraries using IDR-Screen for specific functions can facilitate discovering novel and functional regions of the disordered proteome as well as understand the impact of natural and disease varia...Continue Reading

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Citations

May 24, 2018·Molecular Systems Biology·Muhammad Ali, Ylva Ivarsson
Dec 24, 2018·Molecular Systems Biology·Greg Slodkowicz, M Madan Babu
Sep 15, 2019·Nature Communications·Benedetta BolognesiBen Lehner
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Oct 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Matthew J HenleyAnna K Mapp
Jan 11, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Helios Cárdenas-HernándezElisa Azuara-Liceaga
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May 19, 2021·Cold Spring Harbor Perspectives in Biology·Nicholas Morffy, Lucia C Strader

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Methods Mentioned

BETA
phage display
PCR

Software Mentioned

UPARSE
caretEnsemble
glmnet
fastq
cutadapt
caret
CustomArrays
Heliquest
R
xgboost

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