About

Zhoulai Fu is a tenured Associate Professor at the State University of New York, Korea, with affiliated faculty positions in the Computer Science Department at Stony Brook University and the Electrical and Computer Engineering Department at Virginia Tech. His research focuses on the intersection of Programming Languages, Software Security, and Large Language Models. Prior to his current roles, he held positions at the IT University of Copenhagen in Denmark, the University of California, Davis in the United States, IMDEA in Spain, and INRIA in France, where he earned his PhD. He completed his Bachelor’s and Master’s education at École Polytechnique and Télécom Paris in France, earning the diplôme d’ingénieur (French engineering degree).

Research topics

• Biophysics
• Chemistry
• Biology
• Biochemistry
• Cell biology
• Genetics
• Physics
• Computational biology

Selected publications

• BPS2025 - Structure of the flotillin complex in a native membrane environment

  Biophysical Journal · 2025-02-01

  article1st authorCorresponding
  PublisherDOI

• Structural basis for membrane microdomain formation by a human Stomatin complex

  Nature Communications · 2025-08-12 · 11 citations

  articleOpen accessSenior author

  Biological membranes are not just passive barriers-they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 Å cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a ~12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits C16 symmetry, the C-terminal domains adopt two alternating conformations, producing a symmetry-broken hydrophobic β-barrel pore with local C8 symmetry. The membrane beneath the complex remains flat despite surrounding curvature, indicating localized membrane stiffening. The structure reveals a conserved network of inter-subunit salt bridges that stabilize the assembly. These findings provide a molecular framework for how Stomatin oligomers shape membrane architecture and mechanics, offering insight into their roles in mechanotransduction and diseases such as nephrotic syndrome.

  PublisherOA PDFDOI

• Structure of an LGR dimer, an evolutionary predecessor of glycoprotein hormone receptors

  Nature Communications · 2025-11-28 · 1 citations

  articleOpen access

  Glycoprotein hormones (GpHs) produced in the human pituitary act through receptors (GpHRs) in the gonads to support reproduction and in the thyroid for metabolism. GpHs are heterodimeric cystine-knot proteins; their receptors bind cognate hormones at an extracellular domain and signal through a transmembrane domain to heterotrimeric G proteins. GpHs and GpHRs have co-evolved from invertebrate counterparts. Structures of the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric despite compelling evidence for their functioning as dimers. Here we characterize the homologous receptor from Caenorhabditis elegans. Its biochemical properties are notably similar to those of the thyroid stimulating hormone receptor (TSHR) of humans. Structurally, it is an asymmetric dimer (protomers screw-transformed by 142°/4.1 Å), composed such that only one hormone could bind. This is compatible with the 1:2 asymmetry of negatively cooperative TSH:TSHR complexes and for the transactivation evident from functional complementation of binding-deficient and signaling-deficient GpHRs. By modeling, a symmetrized dimer can bind two hormones as in the 2:2 complexes that support TSHR switches in G-protein usage. Metazoans have evolved endocrine systems that signal through dimerized receptors in response to cognate hormones. These authors characterize a nematode homolog of such human receptors, presenting the cryo-EM structure of an asymmetric dimer that embodies properties of the human receptors.

  PublisherOA PDFDOI

• Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 1 citations

  preprintOpen access

  Summary The glycoprotein hormones of humans, produced in the pituitary and acting through receptors in the gonads to support reproduction and in the thyroid gland for metabolism, have co-evolved from invertebrate counterparts 1,2 . These hormones are heterodimeric cystine-knot proteins; and their receptors bind the cognate hormone at an extracellular domain and transmit the signal of this binding through a transmembrane domain that interacts with a heterotrimeric G protein. Structures determined for the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric 3–6 despite compelling evidence for their functioning as dimers 7–10 . Here we describe the cryo-EM structure of the homologous receptor from a neuroendocrine pathway that promotes growth in a nematode 11 . This structure is an asymmetric dimer that can be activated by the hormone from that worm 12 , and it shares features especially like those of the thyroid stimulating hormone receptor (TSHR). When studied in the context of the human homologs, this dimer provides a structural explanation for the transactivation evident from functional complementation of binding-deficient and signaling-deficient receptors 7 , for the negative cooperativity in hormone action that is manifest in the 1:2 asymmetry of primary TSH:TSHR complexes 8,9 , and for switches in G-protein usage that occur as 2:2 complexes form 9,10 .

  PublisherDOI

• Molecular contacts in self-assembling clusters of membrane proteins

  Proceedings of the National Academy of Sciences · 2025-06-23 · 4 citations

  articleOpen accessCorresponding

  Motivated by recent data pointing to the existence of homo-oligomeric assemblies of membrane proteins called higher-order transient structures, and their apparent role in connecting components of membrane signal pathways, we examine here by cryoelectron microscopy some of the protein-protein interactions that occur in cluster formation. Metabotropic glutamate receptors and HCN ion channels inside clusters contact their neighbors through structured extracellular and intracellular domains, respectively. Other ion channels, including Kv2.1 and Slo1, appear to form clusters through prominent intrinsically disordered sequences in the cytoplasm. These distinct modes of interaction are associated with clusters exhibiting varying degrees of compactness and order. We conclude that nature utilizes a variety of ways to form connections between membrane proteins in self-assembled clusters.

  PublisherOA PDFDOI

• Structural basis for membrane microdomain formation by a human Stomatin complex

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-09 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Biological membranes are not just passive barriers—they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 Å cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a ∼12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits C16 symmetry, the C-terminal domains adopt two alternating conformations, producing a symmetry-broken hydrophobic β-barrel pore with local C8 symmetry. The membrane beneath the complex remains flat despite surrounding curvature, indicating localized membrane stiffening. The structure reveals a conserved network of inter-subunit salt bridges that stabilize the assembly. These findings provide a molecular framework for how Stomatin oligomers shape membrane architecture and mechanics, offering new insight into their roles in mechanotransduction and diseases such as nephrotic syndrome.

  PublisherOA PDFDOI

• An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy

  Journal of Structural Biology · 2024-04-12 · 18 citations

  articleOpen access1st author
  PublisherOA PDFDOI

• Structure of the flotillin complex in a native membrane environment

  Proceedings of the National Academy of Sciences · 2024-07-10 · 59 citations

  articleOpen access1st author

  In this study, we used cryoelectron microscopy to determine the structures of the Flotillin protein complex, part of the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) superfamily, from cell-derived vesicles without detergents. It forms a right-handed helical barrel consisting of 22 pairs of Flotillin1 and Flotillin2 subunits, with a diameter of 32 nm at its wider end and 19 nm at its narrower end. Oligomerization is stabilized by the C terminus, which forms two helical layers linked by a β-strand, and coiled-coil domains that enable strong charge-charge intersubunit interactions. Flotillin interacts with membranes at both ends; through its SPFH1 domains at the wide end and the C terminus at the narrow end, facilitated by hydrophobic interactions and lipidation. The inward tilting of the SPFH domain, likely triggered by phosphorylation, suggests its role in membrane curvature induction, which could be connected to its proposed role in clathrin-independent endocytosis. The structure suggests a shared architecture across the family of SPFH proteins and will promote further research into Flotillin's roles in cell biology.

  PublisherOA PDFDOI

• Author Correction: Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure

  Nature Communications · 2024-07-19

  erratumOpen access

  The original version of this Article contained an error in Fig. 4a and Fig. 4i, and in the figure legend for Fig. 4.In Fig. 4a, the representative image in this panel showing amyloid pathology in Tg-SwDI mice at 6 months of age was inadvertently duplicated from Fig. 4 of a previous publication by the same group 1 .In Fig. 4i, the representative image of capillaries with enlarged amyloid deposits that were observed in 18 months old bigenic Tg-SwDI/Tg2576 mice was an aggregate of representative amyloid laden vessels from three different brain regions used for the quantitative measures presented in panels (j-l) of Figure 4, but this was not demarcated on the figure panel.The representative vessels presented in the original composite image in Fig. 4i were not used for the quantitative comparisons of percentage A immune-positive capillaries (Fig. 4k) nor in measures of capillary amyloid volume (Fig. 4l) between the three brain regions.

  PublisherOA PDFDOI

• Structure of the Flotillin Complex in a Native Membrane Environment

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-09 · 6 citations

  preprintOpen access1st author

  Abstract In this study we used cryo-electron microscopy to determine the structures of the Flotillin protein complex, part of the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) superfamily, from cell-derived vesicles without detergents. It forms a right-handed helical barrel consisting of 22 pairs of Flotillin1 and Flotillin2 subunits, with a diameter of 32 nm its wider end and 19 nm at its narrower end. Oligomerization is stabilized by the C-terminus, which forms two helical layers linked by a β-strand, and coiled-coil domains that enable strong charge-charge inter-subunit interactions. Flotillin interacts with membranes at both ends; through its SPFH1 domains at the wide end and the C-terminus at the narrow end, facilitated by hydrophobic interactions and lipidation. The inward tilting of the SPFH domain, likely triggered by phosphorylation, suggests its role in membrane curvature induction, which could be connected to its proposed role in clathrin-independent endocytosis. The structure suggests a shared architecture across the family of SPFH proteins and will promote further research into Flotillin’s roles in cell biology. Significance statement It is well known that many biochemical processes in cells must occur in localized regions. There are many different ideas about how cells keep processes localized. In this study we demonstrate that Flotillin1 and Flotillin2 co-assemble to form a large, truncated cone shaped cage whose wide end is always attached to a membrane surface and whose narrow end is sometimes attached to a separate membrane. The entire wall of the cage is without holes and is likely impervious even to small molecules, forming a diffusion barrier that can connect membrane systems. The Flotillin cage is thus well suited to isolate biochemical processes. Through membrane attachment, it also alters local membrane curvature, which could influence endocytic and mechanosensory processes.

  PublisherOA PDFDOI

Frequent coauthors

• Joachim Frank

  Columbia University

  27 shared

• Robert A. Grassucci

  Columbia University

  20 shared

• Sandip Kaledhonkar

  Indian Institute of Technology Bombay

  16 shared

• Saikat Chowdhury

  12 shared

• Roderick MacKinnon

  Howard Hughes Medical Institute

  12 shared

• Steven O. Smith

  Stony Brook University

  11 shared

• Yusong R. Guo

  Hong Kong University of Science and Technology

  10 shared

• William E. Van Nostrand

  University of Rhode Island

  10 shared

Education

• Ph.D.

  Columbia University

  2019