Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Investigating the dynamics of LARP1 DM15: A stalwart of ribosome biogenesis regulation

Cassidy, Kevin C. (2021) Investigating the dynamics of LARP1 DM15: A stalwart of ribosome biogenesis regulation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Download (4MB) | Preview


Eukaryotic cells regulate the synthesis of proteins based on environmental conditions such as nutrient abundance or stress. Ribosome biogenesis is a key node in this regulation. La-related protein 1 (LARP1) has recently been identified as a downstream target of mTORC1 that regulates the translation of terminal oligopyrimidine (TOP) mRNAs, which encode all ribosomal proteins. LARP1 phosphorylation by mTORC1 modulates the association of LARP1 with TOP mRNA. Previous studies support both a repressive and stimulatory role for LARP1 in TOP mRNA translation, and its exact role is still unknown; LARP1 has also been shown to stabilize TOP mRNAs. Fully characterizing the role of LARP1 in translation regulation is vitally important because it is upregulated in several carcinomas and is an attractive pharmacological target. The best strategy to pharmacologically target LARP1 depends on the knowledge of how it affects TOP translation, and consequently, how best to modulate its role in that regulation.
Here we used molecular dynamics simulations to investigate the dynamics of the LARP1 DM15 region and provide insight into the dynamics that govern its role in translation regulation. We found that the open or closed state of the cap-binding pocket is correlated with the secondary structure of an adjacent stretch of residues. Additional LARP1 DM15 pockets were identified that have putative allosteric relationships with either the cap- or +1- binding pockets. Co-evolution analysis reveals a potential autoregulatory mechanism via an interdomain interaction with two of these pockets. A breast cancer-associated LARP1 mutation was introduced into one of the pockets in silico, and molecular dynamics simulations revealed the mutation alters the dynamics of both the cap- and +1-binding pockets, potentially altering the ability to bind mRNAs. Lastly, a combination of in silico and in vitro techniques were used to identify compounds that putatively bind LARP1 DM15. Future experiments could utilize the compound hits to investigate the role of LARP1 in TOP mRNA translation, and optimize them for therapeutic use.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Cassidy, Kevin C.kcc35@pitt.edukcc35
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDurrant, Jacob
Committee ChairBerman, Andrea
Committee MemberArndt, Karen
Committee MemberHatfull, Graham
Committee MemberKitzes,
Committee MemberHamelberg,
Date: 8 October 2021
Date Type: Publication
Defense Date: 22 June 2021
Approval Date: 8 October 2021
Submission Date: 5 July 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 187
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: LARP1, DM15, Cancer, Molecular Dynamics Simulation, TOP mRNA
Date Deposited: 08 Oct 2021 20:21
Last Modified: 08 Oct 2023 05:15


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item