TY - JOUR
T1 - Analysis of the inter-domain orientation of tandem RRM domains with diverse linkers
T2 - connecting experimental with AlphaFold2 predicted models
AU - Roca-Martínez, Joel
AU - Kang, Hyun Seo
AU - Sattler, Michael
AU - Vranken, Wim
N1 - Publisher Copyright:
© 2024 The Author(s).
PY - 2024/3/1
Y1 - 2024/3/1
N2 - The RNA recognition motif (RRM) is the most prevalent RNA binding domain in eukaryotes and is involved in most RNA metabolism processes. Single RRM domains have a limited RNA specificity and affinity and tend to be accompanied by other RNA binding domains, frequently additional RRMs that contribute to an avidity effect. Within multi-RRM proteins, the most common arrangement are tandem RRMs, with two domains connected by a variable linker. Despite their prevalence, little is known about the features that lead to specific arrangements, and especially the role of the connecting linker. In this work, we present a novel and robust way to investigate the relative domain orientation in multi-domain proteins using inter-domain vectors referenced to a stable secondary structure element. We apply this method to tandem RRM domains and cluster experimental tandem RRM structures according to their inter-domain and linker-domain contacts, and report how this correlates with their orientation. By extending our analysis to AlphaFold2 predicted structures, with particular attention to the inter-domain predicted aligned error, we identify new orientations not reported experimentally. Our analysis provides novel insights across a range of tandem RRM orientations that may help for the design of proteins with a specific RNA binding mode.
AB - The RNA recognition motif (RRM) is the most prevalent RNA binding domain in eukaryotes and is involved in most RNA metabolism processes. Single RRM domains have a limited RNA specificity and affinity and tend to be accompanied by other RNA binding domains, frequently additional RRMs that contribute to an avidity effect. Within multi-RRM proteins, the most common arrangement are tandem RRMs, with two domains connected by a variable linker. Despite their prevalence, little is known about the features that lead to specific arrangements, and especially the role of the connecting linker. In this work, we present a novel and robust way to investigate the relative domain orientation in multi-domain proteins using inter-domain vectors referenced to a stable secondary structure element. We apply this method to tandem RRM domains and cluster experimental tandem RRM structures according to their inter-domain and linker-domain contacts, and report how this correlates with their orientation. By extending our analysis to AlphaFold2 predicted structures, with particular attention to the inter-domain predicted aligned error, we identify new orientations not reported experimentally. Our analysis provides novel insights across a range of tandem RRM orientations that may help for the design of proteins with a specific RNA binding mode.
UR - http://www.scopus.com/inward/record.url?scp=85183991731&partnerID=8YFLogxK
U2 - 10.1093/nargab/lqae002
DO - 10.1093/nargab/lqae002
M3 - Article
AN - SCOPUS:85183991731
SN - 2631-9268
VL - 6
JO - NAR Genomics and Bioinformatics
JF - NAR Genomics and Bioinformatics
IS - 1
M1 - lqae002
ER -