@article{ADP-ribosyltransferase:10122,
      recid = {10122},
      author = {Lodwick, Jane Elizabeth},
      title = {Structural Insights into Interactions between the Vault  Cage and Components of an ADP-ribosyltransferase System},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2023-12},
      pages = {124},
      abstract = {Among the most intriguing mysteries in contemporary  biology is the functional mechanism of the vault complex.  Renowned for its immense size and arched structure  resembling that of “cathedral vaults,” it is found across  tissue types, cellular compartments, and eukaryotic  species, with a patchy pattern of conservation that  stretches from slime molds to humans. Although work since  vault’s initial discovery in 1986 has failed to define its  precise function, studies of the vault’s primary component  – the major vault protein (MVP) – have provided some clues.  Research observing MVP knockout mice and  condition-dependent changes in MVP expression has  demonstrated vault’s ability to promote cell survival  following exposure to stress. Structures of the giant  oligomeric MVP “cage,” which comprises most of vault’s  mass, have spurred hypotheses that it acts as a molecular  “cargo” transport module and/or signaling scaffold. This  supposition has been bolstered by reports of vault’s  ability to rapidly relocalize to different cellular  compartments following cell perturbation, as well as  observations of heterogeneous density within its Fabergé  egg-like cage. Lacking any enzymatic activity of its own,  the vault cage most likely acts as a relatively inert  vessel. We hypothesized that regulation by additional  molecules is critical to MVP’s ability to accept  transiently associated cargo, move between organelles, and  otherwise mediate cell signaling. Some obvious candidates  to fill these regulatory roles are vault’s understudied  “minor” components: the enzyme poly (ADP-ribose) polymerase  4 (PARP4), the NOD-like protein telomerase component 1  (TEP1), and short non-coding transcripts known as vault  RNAs (vtRNAs), all of which reside within the MVP cage. My  research has therefore sought to explore the roles of  vault’s minor components and expand our understanding of  vault as a multispecies complex. Due to its established  enzymatic activity, I decided to begin by focusing on  PARP4, an ADP-ribosyltransferase that consumes the  metabolite NAD+ to deposit post-translational modifications  (PTMs) onto its target substrates. In Chapter 2, I report  our novel complex structures, which resolve the interface  between MVP and PARP4, as well as a surprising interaction  between MVP and NAD+. Accounts of my initial efforts to  study the cellular function of vault-bound PARP4 are  described in Chapter 3. I summarize my thesis work and its  import in Chapter 4. Additional data supporting the  findings listed in Chapter 2 and preliminary work to  elucidate the structure of the regions of PARP4 that do not  interact with vault can be found in Appendices A and B,  respectively. },
      url = {http://knowledge.uchicago.edu/record/10122},
      doi = {https://doi.org/10.6082/uchicago.10122},
}