Shield and Shuttle: Importins as Protective Chaperones and the Nuclear Transport Mechanism of H2A-H2B

The active transport of macromolecules from the cytoplasm to the nucleus is carried out by a sub-class of Karyopherins called Importins. It was hypothesized back in the early 2000s that importins could have dual functions as 1) nuclear importers and 2) molecular chaperones. This thought stems back to characteristics of importins: they are negatively charged and shuttle positively charged DNA and RNA binding proteins prone to aggregation such as histones, ribosomal proteins, and transcription factors. Nuclear import begins in the cytoplasm where Importins typically recognize a linear pattern of sequences in disordered regions of their cargoes called Nuclear Localization Signals. However, there are growing cases where Importins recognize the cargo's protein fold. Once in the nucleus, cargo release from the Importin is facilitated by a small GTPase, Ran, bound to GTP. Interestingly, there have been many biochemical experiments showing that RanGTP binding is not enough for cargo release of histones H2A-H2B and transcription factors TBP and TFIIB for yeast Importin Kap114. It has been shown that these cargos need both RanGTP and DNA to be fully released from the importin, suggesting these cargos are chaperoned for targeted delivery. Here, I will further discuss how I played a part in unraveling the structural mechanism of the evolutionary conserved H2A-H2B core recognition, chaperoning, and release by Kap114 and its human homolog Imp9. I will also expand upon another importin, Kapβ2, and its mechanism in preventing RNA binding protein FUS, a NLS containing cargo, from phase separating and aggregating, providing strong evidence that importins can function as both protective chaperones and nuclear importers.

Author dc:creator

• Jiou, Jenny

Contributors dc:contributor

• Brautigam, Chad A.
• Chook, Yuh Min
• Wang, Weiwei
• Nam, Yunsun
• D'Arcy, Sheena

• Histones
• Karyopherins
• Nucleosomes

Language dc:language

en

Identifier

1522122357

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10581