TY - JOUR
T1 - N-terminal Domain of TDP43 Enhances Liquid-Liquid Phase Separation of Globular Proteins
AU - Carter, G. Campbell
AU - Hsiung, Chia Heng
AU - Simpson, Leman
AU - Yang, Haopeng
AU - Zhang, Xin
N1 - Funding Information:
We thank support from the Burroughs Wellcome Fund Career Award at the Scientific Interface (X.Z.), Paul Berg Early Career Professorship (X.Z.), Lloyd and Dottie Huck Early Career Award (X.Z.), Sloan Research Fellowship (X.Z.), PEW Biomedical Scholars Program (X.Z.), National Institute of Health R35 GM133484 (X.Z.). We thank Dr. Gang Ning of the Penn State Microscopy Core Facility for collecting the TEM image.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/5/14
Y1 - 2021/5/14
N2 - Liquid-liquid phase separation (LLPS) of proteins is involved in a growing number of cellular processes. Most proteins with LLPS harbor intrinsically disordered regions (IDR), which serve as a guideline to search for cellular proteins that potentially phase separate. Herein, we reveal that oligomerization lowers the barriers for LLPS and could act as a general mechanism to enhance LLPS of proteins domains independent of IDR. Using TDP43 as a model system, we found that deleting its IDR resulted in LLPS that was dependent on the oligomerization of the N-terminal domain (NTD). Replacing TDP43′s NTD with other oligomerization domains enhanced the LLPS proportionately to the state of oligomerization. In addition to TDP43, fusing NTD to other globular proteins without known LLPS behavior also drove their phase separation in a manner dependent on oligomerization. Finally, we demonstrate that heterooligomers composed of NTD-fused proteins can be driven into droplets through NTD interactions. Our results potentiate a new paradigm for using oligomerization domains as a signature to systematically identify cellular proteins with LLPS behavior, thus broadening the scope of this exciting research field.
AB - Liquid-liquid phase separation (LLPS) of proteins is involved in a growing number of cellular processes. Most proteins with LLPS harbor intrinsically disordered regions (IDR), which serve as a guideline to search for cellular proteins that potentially phase separate. Herein, we reveal that oligomerization lowers the barriers for LLPS and could act as a general mechanism to enhance LLPS of proteins domains independent of IDR. Using TDP43 as a model system, we found that deleting its IDR resulted in LLPS that was dependent on the oligomerization of the N-terminal domain (NTD). Replacing TDP43′s NTD with other oligomerization domains enhanced the LLPS proportionately to the state of oligomerization. In addition to TDP43, fusing NTD to other globular proteins without known LLPS behavior also drove their phase separation in a manner dependent on oligomerization. Finally, we demonstrate that heterooligomers composed of NTD-fused proteins can be driven into droplets through NTD interactions. Our results potentiate a new paradigm for using oligomerization domains as a signature to systematically identify cellular proteins with LLPS behavior, thus broadening the scope of this exciting research field.
UR - http://www.scopus.com/inward/record.url?scp=85103645382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103645382&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2021.166948
DO - 10.1016/j.jmb.2021.166948
M3 - Article
C2 - 33744316
AN - SCOPUS:85103645382
SN - 0022-2836
VL - 433
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 10
M1 - 166948
ER -