Data for: Deep mutational scanning of a multi-domain signaling protein reveals mechanisms of regulation and pathogenicity

Multi-domain enzymes can be regulated both by inter-domain interactions and structural features intrinsic to the catalytic domain. The tyrosine phosphatase SHP2 is a quintessential example of a multi-domain protein that is regulated by inter-domain interactions. This enzyme has a protein tyrosine phosphatase (PTP) domain and two phosphotyrosine-recognition domains (N-SH2 and C-SH2) that regulate phosphatase activity through autoinhibitory interactions. SHP2 is canonically activated by phosphoprotein binding to the SH2 domains, which causes large interdomain rearrangements, but autoinhibition is also disrupted by disease-associated mutations. Many details of the SHP2 activation are still unclear, the structure of the active state remains elusive, and hundreds of human variants of SHP2 have not been functionally characterized. Here, we perform scanning mutagenesis on both full-length SHP2 and its isolated PTP domain to examine mutational effects on inter-domain regulation and catalytic ac..., The molecular dynamics data were generated using the Amber Molecular Dynamics Package, as described in the associated manuscript. Data were processed using the CPPTRAJ program within AmberTools. Deep sequencing data are the result of high-throughput peptide display screens, conducted as described in the manuscript. Data were generated using an Illumina MiSeq or NextSeq instrument. Data were processed in three steps: (1) FLASh (https://ccb.jhu.edu/software/FLASH/(opens in new window)) was used for paired-end read merging, (2) CutAdapt (https://cutadapt.readthedocs.io/en/stable/)(opens in new window) was used to trim flanking sequences, and (3) trimmed sequences were translated and counted using in-house Python scripts (https://github.com/nshahlab/2024_Jiang-et-al_SHP2-DMS), , # Data for: Deep mutational scanning of a multi-domain signaling protein reveals mechanisms of regulation and pathogenicity

[https://doi.org/10.5061/dryad.83bk3jb18](https://doi.org/10.5061/dryad.83bk3jb18)

## Associated Preprint:

[https://doi.org/10.1101/2024.05.13.593907](https://doi.org/10.1101/2024.05.13.593907)

## Dates of data collection:

March 2023 to May 2024

## Overview

This dataset contains data from structural and mutational analysis of the signaling enzyme SHP2. The data are clustered into two groups, based on the type of experiment/analysis that generated them. The details of these experiments can be found in the associated preprint. Briefly:

(1) We conducted deep mutational scanning experiments in which we constructed 15 DNA libraries encoding mutations across the SHP2 gene, subjected these to selection for SHP2 function in yeast, and then analyzed the DNA before and after selection by deep sequencing. The data associated with this experiment are FASTQ-format Illum...