Daniel E. Goldberg, M.D., Ph.D.

Internal Medicine
Infectious Diseases
Molecular Microbiology

Molecular Microbiology and Microbial Pathogenesis Program
Biochemistry, Biophysics, and Structural Biology Program
Molecular Cell Biology Program

Research Abstract:

Parasites have evolved many clever ways to infect their hosts and develop within them. Study of these processes at a molecular level should lead to treatment or prevention of parasitic infections that afflict most of humanity. It will also shed light on general principles of biochemistry and cell biology. The organism we are studying is Plasmodium falciparum, a protozoan parasite that causes malaria.

Most of the malaria parasite`s adaptations to intracellular survival are still biological mysteries. Indeed, nearly half of the Plasmodium proteome comprises proteins of unknown function. We are interested in defining the roles of such proteins using a combination of genetic and biochemical approaches.

We are particularly interested in proteases and exported proteins. The parasite exports several hundred effector proteins into its host erythrocyte. What are these proteins doing in the host cell and beyond? How do the proteins get out of the parasite? We believe that one exported protein, histidine-rich protein II, is an important mediator of severe malaria pathogenesis. We are excited about several aspartic proteases called plasmepsins, for which we have identified roles in parasite egress and invasion, as well as in protein export.

Drug resistance is now a major problem. New drugs are desperately needed. Thousands of antimalarial compounds have been identified in chemical library screens but we don`t know their targets. We are using approaches such as whole genome sequencing of resistant mutants, allelic replacement and chemical genetics to define promising new drug targets.

Our work involves a combination of biochemical, genetic, genomic, cell biological, and physiological approaches aimed at understanding the biology of this nefarious organism.

Mentorship and Commitment to Diversity Statement:

Selected Publications:

-Garten M, Beck JR, Roth R, Bleck CKE, Heuser J, Istvan ES, Tenkova-Heuser T, Glushakova S, Goldberg DE*, Zimmerberg J*: Contacting domains segregating a lipid transporter from a solute transporter in the malaria host-parasite interface. Nature Commun 2020; 11: e3825. *co-corresponding authors

-Istvan ES*, Das S*, Corey V, Niles JC, Winzeler EA, Vaidya AB**, Goldberg DE**: Plasmodium falciparum Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis. eLife 2019; 8: e40529. **co-corresponding authors

-Garten M, Glushakova S, Nasamu AS, Niles JC, Zimmerberg J*, Goldberg DE*, Beck J: Exp2 is a nutrient-permeable channel in the vacuolar membrane of Plasmodium and is essential for protein export via PTEX. Nature Microbiol 2018; 3: 1090-1098. *co-corresponding authors

-Nasamu AS, Glushakova S, Russo I, Vaupel B, Oksman A, Kim AS, Fremont D, Tolia N, Beck JR, Meyers MJ, Niles JC, Zimmerberg J, Goldberg DE: Plasmepsins IX and X are essential and druggable mediators of egress and invasion in malaria parasites, Science 2017; 358: 518-522.

-Istvan ES, Mallari J, Corey V, Dharia N, Marshall G, Winzeler EA, Goldberg DE: Esterase mutation is a mechanism of resistance to antimalarial compounds. Nature Commun 2017, 8: 14240.

-Pal P, Daniels B, Oksman A, Diamond M, Klein RS, Goldberg DE: Plasmodium falciparum histidine-rich protein II compromises brain endothelial barriers and may promote cerebral malaria pathogenesis; mBio 2016, 7: e00817-16.

-Sigala PA, Crowley JR, Henderson JP, Goldberg DE: Deconvoluting heme biosynthesis to target blood-stage malaria parasites. eLife 2015, 4: e09143.

-Spillman N, Beck J, Goldberg D: Protein export into malaria parasite-infected erythrocytes: mechanisms and functional consequences; Ann Rev Biochem 2015; 84: 813-841.

-Beck J, Muralidharan V, Oksman A, Goldberg DE: PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes; Nature 2014, 511: 592-595.

-Sigala PA, Goldberg DE: Heme metabolism in Plasmodium; Ann Rev Microbiol 2014; 68: 259-278.

-Ledbetter S, Altenhofen L, Cobbold SA, Istvan ES, Fennell C, Doerig C, Llinas M, Goldberg DE: Plasmodium falciparum responds to amino acid starvation response by entering into a hibernatory state; Proc Natl Acad Sci USA 2012, 109: E3278-E3287. PMC3511138.

-Muralidharan V, Oksman A, Goldberg DE: Heat shock protein 110 maintains the asparagine-rich proteome of Plasmodium falciparum; Nature Comm 2012, 3: 1310. PMC3639100.

-Muralidharan V, Oksman A, Iwamoto M, Wandless TJ, Goldberg DE: Asparagine repeat function in a Plasmodium falciparum protein assessed with a regulatable fluorescence affinity tag; Proc Natl Acad Sci USA 2011, 108: 4411-4416. PMC3060247.

-Istvan ES, Dharia NV, Gluzman I, Winzeler EA, Goldberg DE: Validation of isoleucine utilization targets in Plasmodium falciparum; Proc Natl Acad Sci USA 2011, 108: 1627-1632. PMC3029723.

-Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE: Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte; Nature 2010, 463: 632-636. PMC2826791

Last Updated: 3/23/2021 1:13:26 PM

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