TY - JOUR
T1 - Design of functional intrinsically disordered proteins
AU - Garg, Ankush
AU - González-Foutel, Nicolas S.
AU - Gielnik, Maciej B.
AU - Kjaergaard, Magnus
N1 - Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press.
PY - 2024/3
Y1 - 2024/3
N2 - Many proteins do not fold into a fixed three-dimensional structure, but rather function in a highly disordered state. These intrinsically disordered proteins pose a unique challenge to protein engineering and design: How can proteins be designed de novo if not by tailoring their structure? Here, we will review the nascent field of design of intrinsically disordered proteins with focus on applications in biotechnology and medicine. The design goals should not necessarily be the same as for de novo design of folded proteins as disordered proteins have unique functional strengths and limitations. We focus on functions where intrinsically disordered proteins are uniquely suited including disordered linkers, desiccation chaperones, sensors of the chemical environment, delivery of pharmaceuticals, and constituents of biomolecular condensates. Design of functional intrinsically disordered proteins relies on a combination of computational tools and heuristics gleaned from sequence-function studies. There are few cases where intrinsically disordered proteins have made it into industrial applications. However, we argue that disordered proteins can perform many roles currently performed by organic polymers, and that these proteins might be more designable due to their modularity.
AB - Many proteins do not fold into a fixed three-dimensional structure, but rather function in a highly disordered state. These intrinsically disordered proteins pose a unique challenge to protein engineering and design: How can proteins be designed de novo if not by tailoring their structure? Here, we will review the nascent field of design of intrinsically disordered proteins with focus on applications in biotechnology and medicine. The design goals should not necessarily be the same as for de novo design of folded proteins as disordered proteins have unique functional strengths and limitations. We focus on functions where intrinsically disordered proteins are uniquely suited including disordered linkers, desiccation chaperones, sensors of the chemical environment, delivery of pharmaceuticals, and constituents of biomolecular condensates. Design of functional intrinsically disordered proteins relies on a combination of computational tools and heuristics gleaned from sequence-function studies. There are few cases where intrinsically disordered proteins have made it into industrial applications. However, we argue that disordered proteins can perform many roles currently performed by organic polymers, and that these proteins might be more designable due to their modularity.
KW - biomolecular condensate
KW - biosensor
KW - chaperone
KW - intrinsically disordered protein
KW - linker
KW - protein design
UR - http://www.scopus.com/inward/record.url?scp=85186960248&partnerID=8YFLogxK
U2 - 10.1093/protein/gzae004
DO - 10.1093/protein/gzae004
M3 - Journal article
C2 - 38431892
AN - SCOPUS:85186960248
SN - 1741-0126
VL - 37
JO - Protein Engineering, Design and Selection
JF - Protein Engineering, Design and Selection
M1 - gzae004
ER -