About
Raj Rohatgi is a professor in the Department of Biochemistry at Stanford University. His research group, the Rohatgi Lab, focuses on elucidating the biochemical and cell biological principles that govern signaling pathways at the intersection of developmental biology and cancer. The lab employs a combination of bulk biochemical techniques, such as cell-free reconstitution, and microscopy with novel optical probes to study the dynamics of signal propagation within cells. Their work aims to develop innovative strategies for manipulating these pathways to advance cancer therapies and applications in regenerative medicine.
Research topics
- Biology
- Cell biology
- Biochemistry
- Crystallography
- Evolutionary biology
- Biophysics
- Chemistry
- Genetics
- Computational biology
Selected publications
Overflow data - Design principles of a membrane-spanning ubiquitin ligase. Williams et. al.
Mendeley Data · 2026-05-13
datasetOpen accessRaw data (continued) associated with the above named manuscript
Expanding roles of N-glycosylation in the endoplasmic reticulum
Trends in Cell Biology · 2026-01-01 · 1 citations
articleOpen accessSenior authorDesign principles of a membrane-spanning ubiquitin ligase. Williams et. al.
Mendeley Data · 2026-05-13
datasetOpen accessRaw data associated with the above named manuscript
Multiple modes of cholesterol translocation in the human Smoothened receptor
eLife · 2026-02-09
articleOpen accessSmoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggest two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (∼2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest energetic barrier for cholesterol translocation from the outer leaflet is lower than that from the inner leaflet. Mutagenesis experiments and complementary simulations of SMO mutants validate the role of critical amino acid residues along the translocation pathways. Our data suggests that cholesterol can take either pathway to enter SMO, thus explaining experimental observations in the literature. Thus, our results illuminate the energetics and provide a first molecular description of cholesterol translocation in SMO.
Author response: Multiple modes of cholesterol translocation in the human Smoothened receptor
2026-02-09
peer-reviewOpen accessSmoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggest two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (∼2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest energetic barrier for cholesterol translocation from the outer leaflet is lower than that from the inner leaflet. Mutagenesis experiments and complementary simulations of SMO mutants validate the role of critical amino acid residues along the translocation pathways. Our data suggests that cholesterol can take either pathway to enter SMO, thus explaining experimental observations in the literature. Thus, our results illuminate the energetics and provide a first molecular description of cholesterol translocation in SMO.
2026-02-09
peer-reviewOpen accessSmoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggest two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (∼2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest energetic barrier for cholesterol translocation from the outer leaflet is lower than that from the inner leaflet. Mutagenesis experiments and complementary simulations of SMO mutants validate the role of critical amino acid residues along the translocation pathways. Our data suggests that cholesterol can take either pathway to enter SMO, thus explaining experimental observations in the literature. Thus, our results illuminate the energetics and provide a first molecular description of cholesterol translocation in SMO.
Design principles of a membrane-spanning ubiquitin ligase. Williams et. al.
Mendeley Data · 2026-05-13
datasetOpen accessRaw data associated with the above named manuscript
2026-02-09
peer-reviewOpen accessSmoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggest two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (∼2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest energetic barrier for cholesterol translocation from the outer leaflet is lower than that from the inner leaflet. Mutagenesis experiments and complementary simulations of SMO mutants validate the role of critical amino acid residues along the translocation pathways. Our data suggests that cholesterol can take either pathway to enter SMO, thus explaining experimental observations in the literature. Thus, our results illuminate the energetics and provide a first molecular description of cholesterol translocation in SMO.
2026-02-09
peer-reviewOpen accessSmoothened (SMO), a member of the G Protein-Coupled Receptor superfamily, mediates Hedgehog signaling and is linked to cancer and birth defects. SMO responds to accessible cholesterol in the ciliary membrane, translocating it via a longitudinal tunnel to its extracellular domain. Reaching a complete mechanistic understanding of the cholesterol translocation process would help in the development of cancer therapies. Experimental data suggest two modes of translocation to support entry of cholesterol from outer and inner membrane leaflets, but the exact mechanism of translocation remains unclear. Using atomistic molecular dynamics simulations (∼2 millisecond simulations) and biochemical assays of SMO mutants, we assess the energetic feasibilities of the two modes. We show that the highest energetic barrier for cholesterol translocation from the outer leaflet is lower than that from the inner leaflet. Mutagenesis experiments and complementary simulations of SMO mutants validate the role of critical amino acid residues along the translocation pathways. Our data suggests that cholesterol can take either pathway to enter SMO, thus explaining experimental observations in the literature. Thus, our results illuminate the energetics and provide a first molecular description of cholesterol translocation in SMO.
Overflow data - Design principles of a membrane-spanning ubiquitin ligase. Williams et. al.
Mendeley Data · 2026-05-13
datasetOpen accessRaw data (continued) associated with the above named manuscript
Recent grants
NIH · $618k · 2018
NIH · $2.4M · 2017
NIH · $158k · 2013
NIH · $1.0M · 2012
Unconventional signaling by the R-spondin family of WNT regulators
NIH · $435k · 2020–2022
Frequent coauthors
- 45 shared
Christian Siebold
University of Oxford
- 39 shared
Andres M. Lebensohn
Center for Cancer Research
- 32 shared
Matthew P. Scott
Stanford University
- 29 shared
Ljiljana Milenković
Stanford University
- 23 shared
Ganesh V. Pusapati
Stanford University
- 20 shared
Maia Kinnebrew
Stanford University
- 19 shared
Onn Brandman
Stanford University
- 18 shared
Douglas F. Covey
Labs
Education
MD, Cell Biology
Harvard Medical School
AB, Biochemical Sciences
Harvard College
Ph.D, Medicine
Harvard Medical School
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