top of page
RESEARCH
Active projects:
-
Regulation of protein synthesis during cellular stress
-
Protein Targeting and Import into Mitochondria
Protein targeting to the Endoplasmic Reticulum
Signal recognition particle (SRP) targets membrane and secretory proteins to the endoplasmic reticulum (ER) of all eukaryotic cells. This process takes place while these proteins are still being made on the ribosome. Although SRP is sub-stoichiometric to ribosomes in the cell, it has a strong affinity to translating and non-translating ribosomes. Therefore, it is crucial to control SRP function to prevent erroneous targeting of proteins to the ER membrane. A small ubiquitous protein, known as the nascent polypeptide–associated complex (NAC), regulates the function of SRP in an unknown mechanism. In a recent work, we combined cryo-EM, in-vivo, and single molecule experiments, to reveal how NAC can prevent SRP from binding ribosomes that are synthesizing cytosolic and mitochondrial proteins. Surprisingly, we discovered that NAC at the same time can also recruit SRP to ribosomes translating an ER protein client. Thus, we define the role of NAC as a key sorting factor for nascent chains that helps to ensure the specificity of membrane and secretory protein localization in eukaryotes. See more about this story published in Science.
Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting
Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting
Research: Research
Co-translational protein targeting to membranes by the signal recognition particle (SRP) is a conserved pathway from bacteria to humans. In mammals, SRP and its receptor (SR) have many additional RNA features and protein components compared to the bacterial system. These features were recently shown to play regulatory roles and mutations in SRP were recently identified in patients with congenital neutropenia. A group of disorders that is characterized by low count of neutrophils and is present at birth.
The mammalian SRP targeting process is more complex in mammals as compared to bacteria and thus is mechanistically not well understood. We recently showed how SRP recognizes translating ribosomes with exposed signal sequences and how the GTPase activity of SRP and SR is regulated. Using electron cryo-microscopy, we determined structures of SRP and SRP with its receptor (SR) in complex with the translating ribosome, revealing the specific molecular interactions between SRP and the emerging signal sequence and the elements that regulate its GTPase activity. We propose a molecular mechanism of how eukaryote-specific elements regulate the early and late stages of SRP-dependent protein targeting. See more about this published in Cell Reports and Science Advances.
Molecular mechanism of cargo recognition and handover by the mammalian signal recognition particle
Molecular mechanism of cargo recognition and handover by the mammalian signal recognition particle
bottom of page