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292Molly C. Sutherland, Ph.D.<p>​Assistant Professor<br></p>(302) 831-3021msuther@udel.edu319 Wolf Hall<ul><li>B.S. – University of Maryland, College Park</li><li>Ph.D. – Washington University in St. Louis</li><li>Postdoctoral – Washington University in St. Louis</li></ul><p>​BISC300 – Introduction to Microbiology​</p><p><br></p><p>​Cytochromes <em>c </em>are highly conserved proteins found in humans, other eukaryotes, plants, bacteria and Archaea. Their diverse functions and roles in electron transport chains for respiration and photosynthesis are well studied. However, their biogenesis is less well understood, representing a fundamental biological question and the focus of our research. Cytochrome <em>c </em>biogenesis requires covalent heme attachment via two thioether bonds between the heme vinyls and cysteine thiols at a conserved CXXCH motif (Fig. 1). The requirement for heme attachment makes cytochromes <em>c </em>unique among the cytochromes and is generally agreed to provide high stability and unique properties. Despite their diverse functions and roles in the cell, all cytochromes <em>c</em> are biosynthesized by one of three pathways, termed System I (<em>α</em>, <em>γ</em> Proteobacteria; plant and protozoal mitochondria; Archaea; Fig. 2A), System II (Gram +; cyanobacteria; chloroplasts; <em>ε</em> Proteobacteria; Fig. 2B) and System III (eukaryotic mitochondria, composed of a single enzyme called HCCS). The Sutherland lab focuses on the molecular mechanisms of heme trafficking and attachment in Systems I and II.<br><br></p><p><img src="/content-sub-site/PublishingImages/people/msuther/Fig%201v2%20small.jpg" alt="" style="margin:0px;width:335px;height:181px;" /><br> <strong>Figure 1. Cytochrome <i>c</i> biogenesis.<br></strong>Biogenesis of cytochrome <em>c</em> requires the conserved CXXCH motif of apocytochrome <em>c</em> to be in close proximity to the heme vinyl groups, resulting in the formation of two covalent, thioether bonds between the cysteine thiols and heme vinyl groups.<br><br></p><p> <a href="/content-sub-site/PublishingImages/people/msuther/Fig%202v2.jpg"><img src="/content-sub-site/PublishingImages/people/msuther/Fig%202v2%20small.jpg" alt="Fig 2" style="margin:0px;width:670px;height:211px;" /></a><br><strong>Figure 2. Cytochrome </strong><em><strong>c</strong></em><strong> biogenesis in prokaryotes.<br></strong>(A,B) Models of holocytochrome <em>c</em> biogenesis by (A) System I, Ccm and (B) System II, Ccs. For simplicity, the thioredoxin proteins are not shown. Cytochrome <em>c</em> is indicated in yellow, the synthetase in blue and heme in red.<br><br> </p><p> <em>System I</em>: System I is composed of 8 membrane proteins, CcmABCDEFGH, that are proposed to function in two steps. First, heme is transported from the cytoplasm (CcmABCD) to outside the cell and attached to the heme chaperone (CcmE). Then, heme is trafficked to the holocytochrome <em>c</em> synthetase (CcmFH) and covalently attached to cytochrome <em>c </em>(Fig. 2A).<br></p><p> <em>System II</em>: System II is composed of 2 integral membrane proteins, CcsBA, that function to both transport and attach heme to cytochrome <em>c </em>(Fig. 2B).  <br></p><p>Biogenesis of cytochromes <em>c</em> is essential for cellular survival and conserved across nearly all organisms. Elucidation of the molecular mechanisms of these pathways is critical to understanding bacterial energetics and survival.<br></p><p>Utilizing a recombinant <em>E. coli</em> system for Systems I and II, these integral membrane proteins are affinity tagged, purify with endogenous heme and are functional, allowing for biochemical and genetic studies of these pathways. The Sutherland Lab focuses on the following fundamental questions:<br></p><ul><li>How is heme trafficked by these pathways?</li><li>Can heme binding domains be identified?</li><li>What are the requirements for heme attachment to the cytochrome <em>c</em> CXXCH motif?<br></li></ul><div><br></div><p>We are also interested in the cytochrome <em>c</em> biogenesis pathways as a future target for novel antimicrobials:<br></p><ul><li>What is the role of cytochrome <em>c </em>biogenesis for bacterial survival, particularly in human pathogens?</li><li>Can these fundamental studies lead to novel cytochrome <em>c</em> biogenesis inhibitors?</li></ul><div><em>Graduate Students<b></b></em><b></b><br></div><ul><li><strong>Brett Graver</strong>, Ph.D. Student</li><li><strong>Amber Grunow</strong>, M.S. Student</li><li><strong>Alicia Kreiman</strong>, Ph.D. Student<br></li></ul><div><i>Undergraduate Students</i></div><ul><li><strong>David Hawtof</strong>, undergraduate student, University of Delaware Summer Scholar</li><li><strong>Zobe Nnadike</strong>, undergraduate student, University of Delaware Summer Scholar​<br></li></ul><ul><li><strong>​Sutherland MC</strong><strong>*</strong><strong><sup>+</sup></strong>, Mendez DM<sup>+</sup>, Babbitt SE<sup>+</sup>, Tillman DE, Melnikov O, Tran NL, Prizant NT, Collier AS, Kranz RG. 2021*. <a href="https://pubmed.ncbi.nlm.nih.gov/33973521/">In vitro reconstitution reveals major differences between human and bacterial cytochrome c synthases.</a> <em>eLife</em>:10:e64891.  DOI: 10.7554/ELIFE.64891. *co-corresponding authors, <sup>+</sup>co-first authors (all contributed equally)</li><ul><li><p>​Selected for an eLife Digest – <a href="https://elifesciences.org/digests/64891/the-heme-connection">"The heme connection"</a>​​​​</p></li></ul><li>Gupta D, <strong>Sutherland MC</strong>, Rengasamy K, M​​​​​eacham JM, Kranz RG, Bose A. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31690680">Photoferrotrophs Produce a PioAB Electron Conduit for Extracellular Electron Uptake</a>. <em>mBio</em>. 2019 Nov 5;10(6). pii: e02668-19. doi: 10.1128/mBio.02668-19.<br></li></ul><ul><li><strong>Sutherland MC</strong>, Tran NL, Tillman DE, Jarodsky JM, Yuan J, Kranz RG. 2018. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30563894/">Structure-Function Analysis of the Bifunctional CcsBA Heme Exporter and Cytochrome <em>c</em> Synthetase. </a><i>m</i><em>Bio</em>: 9(6). pii: e02134-18. doi: 10.1128/mBio.02134-18.<br></li></ul><ul><li> <strong> Sutherland MC</strong>, Jarodsky JM, Ovchinnikov S, Baker D, Kranz RG. 2018. <a href="https://www.ncbi.nlm.nih.gov/pubmed/29518410/">Structurally Mapping Endogenous Heme in the CcmCDE Membrane Complex for Cytochrome c Biogenesis. </a><em>J Mol Biol</em>: 430(8):1065-1080. doi: 10.1016/j.jmb.2018.01.022. </li><ul><li><strong><em>Commentary:</em></strong><em> </em>Yuan X, Hamza I. 2018. Cys Links Heme: Stereo-orientation of Heme Transfer in Cytochrome c Biogenesis. <em>J Mol Biol</em>: 430(8):1081–1083. doi:10.1016/j.jmb.2018.02.021</li></ul></ul><p> </p><ul><li> <strong>Sutherland MC</strong>, Rankin JA, Kranz RG. 2016. <a href="https://www.ncbi.nlm.nih.gov/pubmed/27198710/">Heme Trafficking and Modifications during System I Cytochrome c Biogenesis: Insights from Heme Redox Potentials of Ccm Proteins. </a><em>Biochemistry</em>: 55(22):3150-6. doi: 10.1021/acs.biochem.6b00427. </li></ul><p> </p><ul><li>Babbitt SE, <strong>Sutherland MC</strong>, San Francisco B, Mendez DL, Kranz RG. 2015.  <a href="https://www.ncbi.nlm.nih.gov/pubmed/26073510/">Mitochondrial cytochrome c biogenesis: no longer an enigma. </a><em>Trends Biochem Sci</em>: 40(8):446-55. doi: 10.1016/j.tibs.2015.05.006. </li></ul><p> </p><ul><li>Jeong KC, <strong>Sutherland MC</strong>, Vogel JP. 2015. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25582583/">Novel export control of a Legionella Dot/Icm substrate is mediated by dual, independent signal sequences. </a><em>Mol Microbiol</em>: 96(1):175-88. doi: 10.1111/mmi.12928.  </li></ul><p> </p><ul><li>San Francisco B, <strong>Sutherland MC</strong>, Kranz RG. 2014. <a href="https://www.ncbi.nlm.nih.gov/pubmed/24397552/">The CcmFH complex is the system I holocytochrome c synthetase: engineering cytochrome c maturation independent of CcmABCDE. </a><em>Mol Microbiol</em>: 91(5):996-1008. doi: 10.1111/mmi.12510. </li></ul><p> </p><ul><li> <strong>Sutherland MC</strong>, Binder KA, Cualing PY, Vogel JP. 2013. <a href="https://www.ncbi.nlm.nih.gov/pubmed/23762385/"> <em>Reassessing the role of DotF in the Legionella pneumophila type IV secretion system. </em></a><em>PLoS One</em>: 8(6):e65529. doi: 10.1371/journal.pone.0065529. </li></ul><p> </p><ul><li> <strong>Sutherland MC</strong>, Nguyen TL, Tseng V, Vogel JP. 2012. <a href="https://www.ncbi.nlm.nih.gov/pubmed/23028312/">The Legionella IcmSW complex directly interacts with DotL to mediate translocation of adaptor-dependent substrates. </a><em>PLoS Pathog</em>: 8(9):e1002910. doi: 10.1371/journal.ppat.1002910. </li></ul><p> </p><ul><li> <strong>Sutherland MC</strong>, Vogel JP. 2012. <a href="https://www.ncbi.nlm.nih.gov/pubmed/22635996/">Reclamation of ampicillin sensitivity for the genetic manipulation of Legionella pneumophila. </a><em>Appl Environ Microbiol</em>: 78(15):5457-9. doi: 10.1128/AEM.00669-12. </li></ul><p> </p><ul><li>Vincent CD, Friedman JR, Jeong KC, <strong>Sutherland MC</strong>, Vogel JP. 2012. <a href="https://www.ncbi.nlm.nih.gov/pubmed/22694730/">Identification of the DotL coupling protein subcomplex of the Legionella Dot/Icm type IV secretion system. </a><em>Mol Microbiol</em>: 85(2):378-91. doi: 10.1111/j.1365-2958.2012.08118.x. </li></ul><img alt="Molly Sutherland" src="/Images%20Bios/Sutherland-Molly-2022.jpg" style="BORDER:0px solid;" />

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