Endogenous retroviruses represent ancient viral infections that inserted their genetic material into the germline of human ancestors millions of years ago, becoming permanent fixtures within our chromosomes. Among them, HERV-K stands out for its relative activity and expression in contemporary human tissues, notably in pathological states. The Env protein encoded by HERV-K not only adorns the viral particle surface but also manifests on the surface of certain tumor cells and immune cells involved in autoimmune conditions. Despite this significance, structural information about any human endogenous retroviral protein has eluded scientists—until now.

The LJI team, spearheaded by President and CEO Erica Ollmann Saphire, Ph.D., applied cutting-edge cryo-electron microscopy (cryo-EM) techniques to stabilize and visualize the HERV-K Env protein in its elusive pre-fusion state. Envelope glycoproteins are intricately dynamic, existing as metastable complexes poised to dramatically refold upon engaging host cells—a process essential for viral entry. Capturing this fleeting conformation required innovative protein engineering to ‘lock’ HERV-K Env’s shape without disrupting its native architecture, an approach previously employed with success on technically challenging viral proteins such as those from Ebola and Lassa viruses.

The high-resolution images generated reveal an architecture unlike any other retroviral envelope protein solved to date. Unlike the comparatively short and squat trimers characterizing HIV and SIV envelope proteins, HERV-K Env adopts a tall and slender trimeric form. The unique folding pattern, comprising a novel configuration of beta strands and alpha helices interwoven into its functional machinery, sets it apart mechanistically and structurally. This divergence underscores the evolutionary variety among retroviral envelopes and offers fresh insights into the molecular mechanisms driving retroviral fusion and immune recognition.

Notably, this study marks only the third retroviral envelope structure ever solved, and the first from an endogenous human retrovirus, representing a monumental advance in retrovirology. The implications extend beyond structural biology, touching on diseases where aberrant HERV expression has been implicated. For instance, HERV-K Env expression has been documented on the surfaces of breast, ovarian, and other tumor cells. Antibodies directed against this protein could serve as precise markers, discriminating tumor cells from healthy tissue, thereby aiding targeted immunotherapies—such as antibody-drug conjugates or chimeric antigen receptor T-cell (CAR-T) therapies engineered to recognize HERV-K Env-expressing cells.

Moreover, the role of HERV-K Env in autoimmune diseases is gaining attention. Autoimmune conditions like systemic lupus erythematosus and rheumatoid arthritis exhibit upregulated HERV-K Env on patient immune cells, notably neutrophils, which mediate inflammation and tissue damage. The research team demonstrated that their custom-developed monoclonal antibodies could specifically bind these HERV-K Env-expressing immune cells extracted from patients, but not from healthy controls. This suggests a link between HERV-K Env expression and immune dysregulation, highlighting a new landscape for therapeutic intervention aimed at mitigating autoimmune pathology by targeting viral protein components perceived erroneously as threats by the immune system.

The generation and characterization of these monoclonal antibodies against HERV-K Env were pivotal for stabilizing the protein complexes and enabling high-definition structural studies. By identifying antibodies that bind discrete subunits and configurations of the Env trimer, the team dissected the molecular landscape of antibody recognition, an essential step toward rational vaccine design or antibody-based therapies. This panel of antibodies also serves as a valuable toolkit for future diagnostic applications that seek to identify HERV-K-related pathologies at the cellular or molecular level with unprecedented sensitivity.

A remarkable challenge overcome by the researchers was maintaining the HERV-K Env protein in its delicate pre-fusion conformation amid the tendency of such envelope proteins to spontaneously transition to post-fusion states. These rearrangements involve massive structural shifts required for mediating membrane fusion during viral entry. The team’s strategic mutations and antibody-assisted stabilization arrested the protein mid-transition, unveiling structural snapshots critical for understanding viral entry and immune evasion pathways. Such mechanistic insight might help design inhibitors that prevent Env from initiating fusion, curbing pathogenic processes downstream.

This study also represents an exemplar of how advanced imaging modalities like cryo-EM are revolutionizing our understanding of complex biological machines. By producing 3D renderings of HERV-K Env at various functional states—both free on the cell surface and when engaged with neutralizing antibodies—the researchers elucidated the choreography of viral-host interactions at near-atomic resolution. These images reveal not only the static architecture but also dynamic states relevant to infection and immune recognition, guiding future drug discovery focused on these transient but vulnerable stages.

The broader scientific community is watching the unfolding story of HERV-K with growing excitement, as additional diseases and pathological states appear linked to this retroviral relic. With a structurally characterized Env as a molecular beacon, researchers can pivot toward exploring its role in neurodegenerative disorders and other immune-mediated conditions where HERV activity is suspected but mechanistically unclear. This work offers a scaffold for integrative studies merging genomics, immunology, and structural biology to unravel the complexity of human endogenous viruses and their contributions to health and disease.

Ultimately, this groundbreaking research reminds us that humans carry viral ghosts in their genomes—fragments of ancient infections embedded into our DNA across millennia. Far from inert, these endogenous viral elements sometimes wake from dormancy in disease contexts, presenting both challenges and opportunities for science and medicine. The elucidation of HERV-K Env’s structure establishes a foundational platform not only for clinical innovation but also for deeper insights into our evolutionary history and intrinsic biology.

As efforts continue to translate this structural knowledge into therapeutic strategies, including antibody-based diagnostics and targeted immunotherapies, the scientific and medical communities are poised to enter a new era of exploiting endogenous retroviral proteins for human health. The LJI team’s achievement is a testament to perseverance, ingenuity, and multidisciplinary collaboration that merges cutting-edge imaging with molecular engineering to solve one of the longstanding puzzles of viral legacy within the human genome.

Subject of Research: Cells

Article Title: Human endogenous retrovirus K (HERV-K) envelope structures in pre- and post-fusion by cryo-EM

News Publication Date: 27-Aug-2025

Web References:
https://www.science.org/doi/10.1126/sciadv.ady8168

References:
Wilson EM, Moadab F, Hastie KM, Rajamanickam RR, Penalosa PJ, Harkins SS, Parekh D, Hariharan C, Zyla DS, Yu C, Shaffer KCL, Lewis VI, Diaz Avalos R, Mustelin T, et al. Human endogenous retrovirus K (HERV-K) envelope structures in pre- and postfusion by cryo-EM. Science Advances. 2025; DOI:10.1126/sciadv.ady8168.

Image Credits: LJI/Saphire Lab

Keywords: HERV-K, endogenous retrovirus, envelope glycoprotein, structural biology, cryo-electron microscopy, cancer immunotherapy, autoimmune diseases, antibody binding, pre-fusion structure, viral fusion, immunogenetics, molecular imaging

Rhodopsins have long fascinated scientists due to their role as light-activated proteins, primarily known for enabling aquatic microorganisms to harness energy from sunlight and for their pivotal applications in optogenetics—the technique of manipulating neuronal activity with light. However, Kovalev’s investigation into protein databases revealed an intriguing anomaly: a subset of rhodopsins isolated strictly from extraordinarily cold ecosystems bore striking similarities despite vast geographical separation. This surprising genetic and structural conservation hinted at a specialized adaptation strategy, prompting the christening of this family as “cryorhodopsins,” signaling their chillingly unique ecological niche.

Central to the biological and biophysical intrigue is the cryorhodopsins’ remarkable spectral diversity, especially the emergence of novel blue-hued variants. Unlike the more common pink to orange rhodopsins—characterized by absorption of green and blue light—the blue cryorhodopsins exhibit shifts in their molecular architecture that endow them with the ability to absorb and respond to longer wavelengths. This spectral tuning is not trivial; blue light absorption correlates with enhanced tissue penetration and reduced phototoxicity, features highly prized in optogenetic applications aiming for precise and non-invasive modulation of cellular activity.

Kovalev and his collaborators delved deeper, applying cutting-edge structural biology techniques including X-ray crystallography and cryo-electron microscopy under controlled light activation to map the atomic architecture of these proteins at unprecedented resolution. These analyses revealed a subtle but critical rearrangement in the retinal-binding pocket of cryorhodopsins responsible for their blue-shifted absorption properties. By deciphering the atomic-level modifications that confer such optical properties, the team has opened the door to rational design of synthetic blue rhodopsins tailor-made for advanced biomedical and research tools.

Functional assays in cultured neurons further illuminated the dual-switch capabilities of cryorhodopsins. Upon UV light exposure, cells expressing these proteins exhibited inward electrical currents, indicative of activation, whereas sequential illumination with green or red light modulated cellular excitability in opposite directions. This bidirectional control introduces an unprecedented level of finesse to optogenetic manipulation, potentially enabling refined toggling of neural circuits with applications spanning fundamental neuroscience, therapeutic development, and bioengineering.

Beyond their photochemical roles, cryorhodopsins appear to double as sophisticated UV light sensors. Spectroscopic investigations spearheaded by Goethe University Frankfurt scientists uncovered the extremely slow photodynamic response kinetics of cryorhodopsins relative to canonical variants. Such temporal dynamics are characteristic of sensory rather than purely phototransductive proteins, suggesting that these rhodopsins might function as molecular sentinels warning microbes of deleterious UV exposure common in high-altitude or snow-embedded environments.

A particularly groundbreaking aspect of this research is the discovery of a physically coupled small protein whose gene co-localizes with cryorhodopsin genes. Employing artificial intelligence-driven protein structure prediction tools such as AlphaFold, the team proposed a pentameric ring assembly of this minor protein interfacing intimately with the rhodopsin. The working hypothesis posits that upon UV light reception by cryorhodopsin, the small protein acts as a messenger, relocating within the cell to propagate the signal internally. This intricate mechanism exemplifies a sophisticated molecular communication system evolved in microorganisms to survive and adapt in extreme habitats.

The evolutionary impetus behind the puzzling presence and dual functionality of cryorhodopsins remains an open question. Kovalev speculates that rather than cold per se driving these adaptations, it is the intense UV radiation that often accompanies frosty, high-elevation environments that served as the selective force. Thus, these proteins may represent a defensive evolutionary innovation, enabling microbes to detect and respond to harmful radiation exposures, thereby enhancing survival in otherwise hostile ecological niches.

Unlocking these insights was not without formidable obstacles. Cryorhodopsins’ near-identical sequence and structural homogeneity mean that even picometer-scale atomic shifts can dramatically alter their properties, necessitating the use of 4D structural biology techniques integrating time-resolved crystallography and cryo-EM to capture dynamic photoactivation states. Such precision experimental frameworks were vital for revealing how minute structural nuances translate into functional diversity.

Moreover, the proteins’ extreme photosensitivity demanded meticulous sample handling and data acquisition under near-total darkness to prevent premature activation. Collaboration across multiple international research institutions, coupled with access to specialized beamlines like EMBL Hamburg’s P14, were essential components enabling the successful structural characterization and functional assays of these elusive molecules.

While cryorhodopsins have yet to be harnessed as practical optogenetic tools, their early characterization as “cellular power switches” sets a compelling precedent. Kovalev envisions future engineered variants optimized for high efficiency, reversible control, and compatibility with deep tissue applications. Such advancements hold the promise to transform neuroscience research and pave the way for innovative therapeutic approaches, including improved optical cochlear implants and interventions in neurological disorders.

The discovery of cryorhodopsins epitomizes the transformative potential of combining bioinformatics, AI-driven modeling, advanced structural techniques, and functional validation in living cells. It also underscores the importance of exploring remote and extreme environments, where nature’s molecular ingenuity often reveals novel biotechnological treasures waiting to be uncovered and harnessed for human benefit.

Subject of Research: Cells
Article Title: CryoRhodopsins: a comprehensive characterization of a group of microbial rhodopsins from cold environments
News Publication Date: 4-Jul-2025
Web References: http://dx.doi.org/10.1126/sciadv.adv1015
Image Credits: Daniela Velasco/EMBL
Keywords: Microbiology, Signal transduction, Cell biology

The Protein Society, a leading authority in the realm of protein research, recently announced the prestigious winners of the 2025 Protein Society Awards. This recognition is a highlight of the society’s commitment to advancing the field of protein science and will take place during the 39th Annual Symposium scheduled from June 26 to June 29, 2025, in San Francisco. The event promises to be a scholarly gathering featuring plenary talks from award winners who have made groundbreaking contributions to protein science. Their scientific achievements, detailed by their nominators, reflect a profound impact on various aspects of protein research and its implications in biological systems.

One of the most esteemed accolades this year, the Christian B. Anfinsen Award, is dedicated to recognizing exceptional technological advancements and methodological innovations in protein science. The recipient, Professor Jan Steyaert from Vrije Universiteit Brussel and the VIB, stands at the forefront of nanobody technology. His work in applying nanobodies as scaffolds has facilitated the exploration of the structures and functional mechanisms of vital proteins such as G protein-coupled receptors (GPCRs). This kind of research exemplifies how innovative techniques can enhance our understanding of protein behaviors and interactions, ultimately leading to potential therapeutic applications.

Similarly, the Carl Brändén Award is designed to honor contributions that go beyond individual research, encapsulating educational and service-oriented endeavors within the scientific community. Professor James Fraser from the University of California, San Francisco, is this year’s distinguished recipient. His pioneering work in developing room temperature X-ray data collection techniques has revolutionized the study of proteins. By employing ensemble modeling methods, Dr. Fraser has not only enhanced our ability to study proteins more effectively but has also made substantial strides in educational initiatives that promote collaborative learning within the scientific community.

Continuing the theme of contributions that transcend basic research, the Dorothy Crowfoot Hodgkin Award acknowledges those who have significantly influenced biological sciences through protein science. Professor Andy LiWang from the University of California, Merced, is the proud recipient. His meticulous investigations into the mechanisms of circadian rhythms have deepened our understanding of biological timekeeping systems. By elucidating how proteins and cells can sense and respond to time, Dr. LiWang has laid groundwork that could lead to innovations in chronobiology and its applications in medicine.

Another noteworthy recognition is the Marie Maynard Daly Award, which underscores groundbreaking research that bridges protein science and human health. This year, Professor Yuh Min Chook from UT Southwestern Medical Center received this honor for her impactful work in studying nucleo-cytoplasmic transport mechanisms. Her research has significant implications for understanding cellular function and has led to the identification of critical processes that facilitated the FDA’s approval of a novel cancer drug. This intersection of fundamental science and practical health solutions is a prime example of how protein research can lead to tangible advancements in medical therapies.

The Emil Thomas Kaiser Award, driven by individual contributions to cancer research and protein chemistry, was awarded to Dr. Brian Kuhlman from the University of North Carolina at Chapel Hill. His groundbreaking work in protein structural modeling and de novo protein design has furthered our capacity to understand protein-protein interactions and engineering. By integrating methods like deep learning, Dr. Kuhlman’s contributions represent a significant leap in predicting protein stability and energetics, providing crucial insights into protein functionality.

In a similar vein, the Hans Neurath Award shines a spotlight on recent contributions of exceptional merit to basic protein research. Professor Antonina Roll Mecak from NIH – NINDS has made significant headway in understanding the dynamic properties of microtubules, which are essential components supporting cellular structure and function. Through her explorations of the tubulin code and her discoveries concerning microtubule nanodamage and repair mechanisms, Roll Mecak’s work has implications spanning from basic biology to therapeutic development.

The Stein & Moore Award acknowledges sustained high-impact research contributions in protein science. Professor Timothy Springer from Harvard Medical School is this year’s recipient, widely revered for his foundational discoveries regarding T-cell responses and immunological pathways. His groundbreaking research has led not only to a better understanding of cell recognition processes but has also paved the way for innovative therapeutics targeting immune responses, thus influencing treatments for various conditions, including psoriasis and ulcerative colitis.

The Protein Science Young Investigator Award, which recognizes emerging talent in protein research, saw two exemplary scientists honored this year: Professor Christopher Barnes from Stanford University and Professor Jamie Spangler from Johns Hopkins University. Both of their works illustrate the dynamism and potential of young scientists within the field. Dr. Barnes’s contributions have redefined approaches to infectious diseases through advanced structural biology, while Dr. Spangler’s innovative molecular immunoengineering is crafting new avenues for therapeutic protein design, showcasing the future of protein research.

Over the course of the symposium, attendees can expect to engage with the award recipients, gaining insights from their plenary talks while networking with fellow researchers, exhibitors, and sponsors. As the 39th Annual Symposium approaches, anticipation builds around the potential collaborations and revolutionary ideas that will emerge from this gathering, aligning with The Protein Society’s objectives to foster communication and cooperation within the scientific community.

The Protein Society has long been an advocate for the advancement of protein science, providing diverse forums for discussion and dissemination of important research outcomes since its establishment in 1986. Through its flagship journal, Protein Science, and the facilitation of education for early-career scientists, the Society continues to represent a wide array of professionals dedicated to exploring the complexities of proteins and their myriad roles across biological systems.

As we look ahead to the symposium and the insights to be shared by distinguished scientists, it is clear that the field of protein science stands at a pivotal moment, poised to make further strides that will enhance our understanding of biological phenomena, improve research methodologies, and ultimately pave the way for groundbreaking health solutions.

The awards served not only as a celebration of current achievements but also as an inspiration for future generations of researchers continuing to explore the untapped potential that lies within protein science, acknowledging the hard work and dedication required to drive the field forward towards new horizons.

Subject of Research: Advances in Protein Science
Article Title: Celebrating Innovation and Excellence in Protein Research: 2025 Protein Society Awards Announced
News Publication Date: [To be filled as per publication]
Web References: [To be filled as per publication]
References: [To be filled as per publication]
Image Credits: [To be filled as per publication]

Keywords: Protein Research, Protein Science, Nanobodies, Circadian Biology, Nucleo-Cytoplasmic Transport, Immunoengineering, Protein Design, Basic Research, Clinical Applications, Structural Biology, Scientific Awards, Annual Symposium.