- Title Information
- Title
- The Allosteric Regulation of Macrophage Migration Inhibitory Factor
- Type of Resource (primo)
- dissertations
- Name:
Personal
- Name Part
- Skeens, Erin
- Role
- Role Term:
Text
- creator
- Name:
Personal
- Name Part
- Lisi, George
- Role
- Role Term:
Text
- Advisor
- Name:
Personal
- Name Part
- Fawzi, Nicolas
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Jogl, Gerwald
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Ayala, Alfred
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Massi, Francesca
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. Department of Molecular Biology, Cell Biology and Biochemistry
- Role
- Role Term:
Text
- sponsor
- Origin Information
- Copyright Date
- 2025
- Physical Description
- Extent
- xiv, 207 p.
- digitalOrigin
- born digital
- Note:
thesis
- Thesis (Ph. D.)--Brown University, 2025
- Genre (aat)
- theses
- Abstract
- Abstract of The Allosteric Regulation of Macrophage Migration Inhibitory Factor, by Erin Skeens, Ph.D., Brown University, October 2025
Macrophage Migration Inhibitory Factor (MIF) is a ubiquitous immunoregulatory protein involved in the pathophysiology of inflammation, with several distinct enzymatic activities and an expansive interactome that broaden its biological impact. However, the biophysical mechanisms that facilitate its non-overlapping functions remain elusive. Further, MIF is implicated in a broad range of diseases marked by chronic inflammation, positioning it as a compelling target for the development of therapeutics, and necessitating a comprehensive characterization of the structure-function axis of MIF to inform drug discovery efforts. Allostery, a regulatory process that transmits chemical information over long molecular distances within a protein, has emerged as a key determinant of the underlying mechanisms mediating MIF function. This dissertation provides foundational studies of the allosteric regulation of MIF, leveraging the sensitivity of solution NMR spectroscopy to visualize the MIF structure and its dynamics with atomic resolution, which are critical for the propagation of long-range allosteric communication. This work identified allosteric residues and networks that control MIF enzymatic and signaling functions, and how modulation of these allosteric sites impacts function. A pathway of residues comprising Pro1, Met2, His62, and Tyr99 was shown to control MIF tautomerase function, with Tyr99 revealed as a critical allosteric mediator that functionally couples MIF tautomerase activity with the activation of its pro-inflammatory cell surface receptor, CD74. This work also explored the impacts of pro-inflammatory stimuli on the biophysical properties and biomolecular interactions of MIF. MIF was shown to undergo structural perturbation and altered dynamics under hydrogen peroxide-treated conditions, revealing latent allosteric sites at Lys66 and Cys80 that mediate its conversion to an oxidized conformation. Further, oxidation of MIF with hypochlorous acid revealed selective binding to anti-oxMIF antibodies, and importantly, to its CD74 receptor, suggesting a redox-driven mechanism to its inflammatory signaling function. Collectively, the work described in this dissertation identified and characterized novel sites that mediate MIF function, including those critical to MIF in proinflammatory environments, thus broadening the druggable landscape of MIF towards translational impact.
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00831961")
- Topic
- Biochemistry
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01079711")
- Topic
- Proteins
- Subject
- Topic
- Structural biology
- Language
- Language Term (ISO639-2B)
- English
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20251201