Peter Walter (born December 5, 1954) is a German-American molecular biologist and biochemist. He is currently the Director of the Bay Area Institute of Science at Altos Labs and an emeritus professor at the Department of Biochemistry and Biophysics of the University of California, San Francisco (UCSF). [2] [3] He was a Howard Hughes Medical Institute (HHMI) Investigator until 2022.
Walter was born and raised in West Berlin in 1954. His parents owned a pharmacy, and he was drawn to chemistry at a young age. [4] He entered the Free University of Berlin in 1973 to study chemistry, but the rigid way of teaching science did not engage him. Instead, Walter became interested in biochemistry, which studies the chemistry of cells. [4] [5]
In the last year of his Vordiplom (equivalent to a BSc) in 1976, he went on exchange to Vanderbilt University and conducted research under Thomas M. Harris at the Department of Chemistry on the biosynthetic pathway of slaframine, a fungal alkaloid that is toxic to cows. [6] Eventually, Walter completed his MSc in Vanderbilt in 1977. [1]
At the encouragement of Stanford Moore, a biochemistry professor at Rockefeller University and a trustee of Vanderbilt, Walter applied for the PhD programme at Rockefeller. [6] He was placed on the waiting list, but after an accepted student went to Harvard University instead, was offered his place in 1977. [4] [5] He took his PhD under Günter Blobel, and obtained the degree in 1981. [1]
After receiving his PhD, Walter stayed at Rockefeller University as a postdoctoral fellow for a year, then became an assistant professor at the Laboratory of Cell Biology at Rockefeller. [1]
In 1983, he moved to the Department of Biochemistry and Biophysics of the University of California, San Francisco (UCSF) as an assistant professor. Walter was promoted to associate professor in 1986 and then full professor in five years later. [1] He was chair of the Department of Biochemistry and Biophysics of UCSF between 2001 and 2008. [7]
Walter became a Howard Hughes Medical Institute investigator in 1997, and served as the president of the American Society for Cell Biology in 2016. [8]
In 2021, there were reports that he would be joining Altos Labs, a new biotechnology company which reportedly focuses on anti-aging research. [9] [10] The next year, he retired from UCSF and the Howard Hughes Medical Institute in 2022, [11] [12] and joined Altos Labs as the Director of the Bay Area Institute of Science when the company officially launched. [13] [14]
Walter currently sits on the Scientific Advisory Board of the Zentrum für Molekulare Biologie der Universität Heidelberg of Heidelberg University. [15]
Walter is a coauthor of the widely used textbook Molecular Biology of the Cell . [16]
During his PhD at Günter Blobel's group, Walter purified a protein complex required for moving proteins out of the endoplasmic reticulum (ER) [17] and showed the complex selectively recognizes newly synthesized secretory proteins. [18] He later confirmed the complex is in fact a nucleoprotein and identified the RNA component essential for the complex's function. He also named the complex signal recognition particle (SRP). [19]
By the time Walter joined the University of California, San Francisco (UCSF), researchers have established a connection between misfolded proteins in the ER and increased expression of a protein called BiP, which is a chaperone protein that helps other proteins fold correctly. This pathway is termed the unfolded protein response (UPR). However, how cells sense misfolded proteins and relays this information to the cell nucleus to increase the production of UPR-target proteins remains unclear. [20]
In 1993, working on baker's yeast, Walter found a gene, IRE1 , which encodes a kinase. The IRE1 protein is located across the ER membrane, so a part of it can detect unfolded proteins inside the ER and the other part can phosphorylate proteins outside of the ER. [21] The same year, Kazutoshi Mori, at the time a postdoctoral fellow at the University of Texas Southwestern Medical Center, independently made the same discovery. [22]
Walter and Mori next independently sought the phosphorylation target of the IRE1 protein. Theoretically, upon phosphorylation, this target will enter the cell nucleus and increase the production of UPR-target proteins. Both of them arrived at the same gene, HAC1, in 1996. [23] [24] This discovery, however, was unexpected as the HAC1 protein is produced only after IRE1 detects unfolded proteins, meaning the protein is not present to be phosphorylated by IRE1.
This difference was mitigated by the finding of Mori and Walter that after IRE1 senses unfolded proteins, it splices the HAC1 precursor mRNA, which is transcribed from the HAC1 gene, resulting in a mature mRNA that is translated into the HAC1 protein. [25] [26] Walter also discovered the phosphorylation target of IRE1, which turned out to be another IRE1 molecule, a process known as trans-autophosphorylation, [27] and also the enzyme stitching the spliced precursor HAC1 mRNA together. [28]
In 2013, Walter's group identified a molecule that inhibits the integrated stress response (ISR). The ISR is the cell's response to stresses such as viral infection, ultraviolet light and the accumulation of unfolded and misfolded proteins. ISR activates the EIF2α protein, reducing most protein synthesis and increasing the production of some regulatory molecules. [29] His group found the inhibitor reversed EIF2α activation, and named it ISRIB for "integrated stress response inhibitor". Remarkably, they found mice injected with ISRIB had improved memory. [30] ISRIB was licensed to Alphabet subsidiary Calico in 2015. [31]
Walter is married to Patricia Caldera-Muñoz, [53] whom he met in New York City during his PhD years at Rockefeller University and when Caldera-Muñoz was a chemistry PhD student at New York University. [5] Before retiring, Caldera-Muñoz worked at the University of California, San Francisco (UCSF) Science and Health Education Partnership, where she coordinated outreach to local science teachers. [54] [55]
Walter was diagnosed with neck cancer in 2009. [56]
The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.
Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.
The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.
A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, most type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.
Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.
X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene. The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP1 protein is a transcription factor that regulates the expression of genes important to the proper functioning of the immune system and in the cellular stress response.
Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.
Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.
DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.
Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.
The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.
In cell biology, membrane bound polyribosomes are attached to a cell's endoplasmic reticulum. When certain proteins are synthesized by a ribosome they can become "membrane-bound". The newly produced polypeptide chains are inserted directly into the endoplasmic reticulum by the ribosome and are then transported to their destinations. Bound ribosomes usually produce proteins that are used within the cell membrane or are expelled from the cell via exocytosis.
The bZIP intron RNA motif is an RNA structure guiding splicing of a non-canonical intron from bZIP-containing genes called HAC1 in yeast, XBP1 in Metazoa, Hxl1 or Cib1 in Basidiomycota and bZIP60 in plants. Splicing is performed independently of the spliceosome by Ire1, a kinase with endoribonuclease activity. Exons are joined by a tRNA ligase. Recognition of the intron splice sites is mediated by a base-paired secondary structure of the mRNA that forms at the exon/intron boundaries. Splicing of the bZIP intron is a key regulatory step in the unfolded protein response (UPR). The Ire-mediated unconventional splicing was first described for HAC1 in S. cerevisiae.
Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells, which can contribute to the development of both type I and type II diabetes.
Kazutoshi Mori is a Japanese molecular biologist known for research on unfolded protein response. He is a professor of Biophysics at the Graduate School of Science, Kyoto University, and shared the 2014 Albert Lasker Basic Medical Research Award with Peter Walter for discoveries concerning the unfolded protein response — an intracellular quality control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures.
David Ron FRS is a British biochemist.
David Domingo Sabatini is an Argentine-American cell biologist and the Frederick L. Ehrman Professor Emeritus of Cell Biology in the Department of Cell Biology at New York University School of Medicine, which he chaired from 1972 to 2011. Sabatini's major research interests have been on the mechanisms responsible for the structural complexity of the eukaryotic cell. Throughout his career, Sabatini has been recognized for his efforts in promoting science in Latin America.
The bZIP intron saccharomycetales is an unconventional bZIP intron located in the HAC1 mRNA in most budding yeast belonging to Saccharomycetales order. The structure consists of two hairpins with their loop regions defining 5’ and 3’ splice sites and a long, poorly conserved sequence separating them. In some species this poorly conserved region can pair with the 5’ UTR of the HAC1 mRNA forming a pseudoknot, which stalls the translation. The unconventional splicing is performed by an endoribonuclease Ire1 in response to ER stress and it was first shown in Saccharomyces cerevisiae.
Gia Voeltz is an American cell biologist. She is a professor of Molecular, Cellular and Developmental Biology at the University of Colorado Boulder and a Howard Hughes Medical Institute Investigator. She is known for her research identifying the factors and unraveling the mechanisms that determine the structure and dynamics of the largest organelle in the cell: the endoplasmic reticulum. Her lab has produced paradigm shifting studies on organelle membrane contact sites that have revealed that most cytoplasmic organelles are not isolated entities but are instead physically tethered to an interconnected ER membrane network.
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