Kap-[beta]2 Recognition of Cargoes Involved in Neurodegenerative/Neurodevelopmental Diseases

Karyopherin β2 is a nuclear-import receptor that transports many RNA-binding proteins into the nucleus by recognizing within the cargoes a unique nuclear-localization signal known as the PY-NLS. Several of Kapβ2 cargoes are mutated in neurological diseases. Two such proteins of interest to my research are the Fused in Sarcoma (FUS) and the HNRNPH2 proteins that are mutated in familial ALS and Bain disease, respectively. I studied the interactions of Kapβ2 with HNRNPH2, which is mutated in the neurodevelopmental disease known as Bain disease. Mutations in HNRNPH2 were first found in 2016, and, since then, 14 mutations have been linked to this disorder, with several mutations found within its PY-NLS. We have observed that these mutations cause mislocalization of the cargo to stress granules in the cytoplasm. I performed biophysical and structural studies and found that the HNRNPH2 has a new type of epitope not observed before. Furthermore, I observed that this new epitope is essential for HNRNPH2 recognition. These findings are consistent with several mutations found within this epitope that are linked to Bain disease. I also studied two FUS mutations, FUS(R495X) and FUS(P525L), that cause a severe type of ALS. First, I found that, in the absence of the PY-NLS like in FUS(R495X) mutation, Kap2 recognizes the arginine-glycine-glycine (RGG) regions of FUS as a secondary mechanism for nuclear transport. Lastly, together with the Shorter Lab, I characterized an engineered mutant Kap2 that can recognize FUS(P525L), transport it into the nucleus and decrease FUS aggregation more efficiently. I performed biophysical and structural studies in some of these engineered Kap2 to explain how these mutants improve interactions with the ALS-causing mutant FUS(P525L). We found that engineered Kap2 makes more contacts with FUS(P525L), rescuing binding activity.

Author dc:creator

• González Castro, Abner Josué

Contributors dc:contributor

• Rizo-Rey, José
• Brautigam, Chad A.
• Joachimiak, Lukasz
• Chook, Yuh Min

• Karyopherins
• Nuclear Localization Signals
• RNA-Binding Proteins
• beta Karyopherins

Language dc:language

en

Identifier

1522122351

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10580