Disordered Motifs and Domains in Cell Control
Monday Speaker Abstracts
Decision Making and Molecular Interplay during Protein Biogenesis
Shu-ou Shan
, Aileen Ariosa, Jae Ho Lee.
Caltech, Pasadena, USA.
Accumulating data show that the ribosome exit site is a crowded environment where a variety of
protein biogenesis factors interact with a nascent protein. Accurate decision-making must be
made at the ribosome exit site to ensure that the nascent protein engage the correct factors, and
thus enter the proper biogenesis pathway. The molecular mechanisms by which these decisions
are made have remained elusive. To address this question, we investigated the molecular
interplay between the signal recognition particle (SRP), a conserved protein-targeting machine
that mediates the localization of proteins to the cellular membrane, and trigger factor (TF), a
major co-translational chaperone in bacteria. The results reveal multiple mechanisms by which
TF influences cargo selection by the SRP, and provide a conceptual framework to understand
molecular interplay in the crowded environment at ribosome exit site.
Protein Disorder and Polybivalency in Allosteric Regulation of Large Molecular Machines
Elisar Barbar
, Afua Nyarko, Jie Jing.
Oregon State University, Corvallis, USA.
Cytoplasmic dynein is an essential microtubule-based motor that controls diverse cellular
processes ranging from mitotic spindle assembly to axonal transport. An intriguing feature of this
multi-subunit complex is the regulation of its activity and various functions depends on multiple
protein complexes that bind at the intrinsically disordered N-terminus of the intermediate chain
subunit, located quite distant from the motor end of the complex. The N-terminal domain of the
intermediate chain IC is also the site of binding to LC8, a dimeric protein known to promote
structural organization of its disordered partners by enhancing either the partner self-association
or binding affinity to other dimeric proteins. This work combines NMR and isothermal titration
calorimetry to investigate the residue level allosteric communication between yeast orthologs of
LC8 (Dyn2) and the p150Glued subunit (Nip100) of the dynein regulator, dynactin. The N-
terminal domain of yeast IC (Pac11) is primarily a disordered monomer except for a single alpha
helix (SAH) that projects as an elongated structure and forms the recognition site for Nip100.
The SAH domain is followed by two recognition sites for Dyn2 separated by a 20-residue linker
that includes a nascent helix. Dyn2 binding induces structural changes in Pac11 localized to the
linker helix which interestingly is the same helix that is significantly affected by Nip100 binding.
We propose that multiple Dyn2 sites shift the population states of disordered Pac11 to an aligned
active conformation but rather than enhancing binding of Pac11 to Nip100, they facilitate
allosteric regulation by aligning the linker helix that is part of the Nip100 binding dynamic
network. The conservation of protein disorder among IC orthologs underscores the importance of
structural transitions triggered by bivalent light chains for propagation of long range
conformational changes.
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