proteins Archives - Sanford Burnham Prebys

Tag: proteins

Institute News

How a protein component of nuclear pore complexes regulates development of blood cells and may contribute to myeloid disorders

AuthorCommunications
Date

June 5, 2024

A computer graphic depicts a nuclear pore in a eukaryotic cell. Nuclear pores are large protein complexes that span the nuclear membrane and allow the movement of molecules, such as proteins, RNAs, and other molecules between the nucleus and the cell’s cytoplasm. Image courtesy of M. Towler and J. Aitken, Wellcome Collection.
Computer graphic depicts a nuclear pore in a eukaryotic cell. Nuclear pores are large protein complexes that span the nuclear membrane & allow the movement of molecules, such as proteins, RNAs, & other molecules between the nucleus & the cell’s cytoplasm.

Nuclear pore complexes (NPCs) are channels composed of multiple proteins that ferry molecules in and out of the nucleus, regulating many critical cellular functions, such as gene expression, chromatin organization and RNA processes that influence cell survival, proliferation, and differentiation.

In recent years, new studies, including work by Maximiliano D’Angelo, PhD, associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, have noted that NPCs in cancer cells are different, but how these alterations contribute to malignancy and tumor development—or even how NPCs function in normal cells—is poorly understood.

In a new paper, published June 5, 2024 in Science Advances, D’Angelo with first author Valeria Guglielmi, PhD, and co-author Davina Lam, uncover Nup358, one of roughly 30 proteins that form the NPCs, as an early player in the development of myeloid cells, blood cells that if not formed or working properly leads to myeloid disorders such as leukemias.

The researchers found that when they eliminated Nup358 in a mouse model, the animals experienced a severe loss of mature myeloid cells, a group of critical immune cells responsible for fighting pathogens that are also responsible for several human diseases including cancer. Notably, Nup358 deficient mice showed an abnormal accumulation of early progenitors of myeloid cells referred as myeloid-primed multipotent progenitors (MPPs).

“MPPs are one of the earliest precursors of blood cells,” said D’Angelo. “They are produced in the bone marrow from hematopoietic stem cells, and they differentiate to generate the different types of blood cells.

Maximiliano D’Angelo and Valeria Guglielmi

“There are different populations of MPPs that are responsible for producing specific blood cells and we found that in the absence of Nup358, the MPPs that generate myeloid cells, which include red blood cells and key components of the immune system, get stuck in the differentiation process.”

Fundamentally, said Gugliemi, Nup358 has a critical function in the early stages of myelopoiesis (the production of myeloid cells). “This is a very important finding because it provides insights into how blood cells develop, and can help to establish how alterations in Nup358 contribute to blood malignancies.”

The findings fit into D’Angelo’s ongoing research to elucidate the critical responsibilities of NPCs in healthy cells and how alterations to them contribute to immune dysfunction and the development and progression of cancer.

“Our long-term goal is to develop novel therapies targeting transport machinery like NPCs,” said D’Angelo, who recently received a two-year, $300,000 Discovery Grant from the American Cancer Society to advance his work.

This research was supported in part by a Research Scholar Grant from the American Cancer Society (RSG-17-148-01), the Department of Defense (grant W81XWH-20-1-0212) and the National Institutes of Health (AI148668).

The study’s DOI is 10.1126/sciadv.adn8963.

Institute News

Without this protein, tuberculosis is powerless

AuthorMiles Martin
Date

May 9, 2022

Illustration of a tuberculosis-infected lung against a backdrop of tuberculosis bacteria

A new study from the lab of Francesca Marassi, PhD could help reveal new treatments for one of the world’s deadliest pathogens.

Sanford Burnham Prebys researchers have uncovered the structure of an important protein for the growth of tuberculosis bacteria. The study, published recently in Nature Communications, sheds light on an unusual metabolic system in tuberculosis, which could help yield new treatments for the disease and help make existing therapies more effective.

“Molecular discoveries like this give us valuable insight into how these bacteria survive, which is important in terms of finding cures for tuberculosis, and for other areas of health and biology,” says James Kent, a PhD candidate working in Marassi’s lab. “For example, bacteria in this family pose problems in both human health and agriculture, such as leprosy and bovine tuberculosis.”

Tuberculosis caused 1.5 million deaths in 2020 according to the World Health Organization, and this figure is expected to increase in the coming years due to the impact of the COVID-19 pandemic.

Stealing iron has its risks
The new protein, called Rv0455c, is part of a complex transportation system in Mycobacterium tuberculosis. Rv0455C helps the bacteria take up iron from the host cells they infect. This process is essential to their growth and replication.

“They produce these very small molecules called siderophores and send them out of the cell, where they bind to iron and bring it back in,” says Kent. “Rv0455C seems to be essential for secreting these molecules.”

An important step of this iron-uptake process is recycling the siderophores so they can be used again. When this process is interrupted, the leftover molecules can accumulate and poison the cell.

The study found that without Rv0455c, tuberculosis bacteria cannot secrete siderophores, which severely impairs their replication. Bacteria without Rv0455c also experienced poisoning from unrecycled siderophores. 

And while this delicate system can be interrupted by blocking previously known genes, eliminating Rv0455c does it much more efficiently.

“This seems to be the first piece of evidence that there is a single protein in this system that could be targeted by a new class of tuberculosis drugs,” adds Kent.

Structure determines function
Kent’s role in the study was to piece together the structure of the protein, which had posed a significant challenge to the researchers. Revealing the detailed structure of a protein is a critical part of understanding its function.

“The process of figuring out the structure of a protein can be time consuming and requires precise optimization of many conditions,” says Kent. “This protein is small, but it is still a three-dimensional object moving in three-dimensional space, and the way it’s shaped will affect what it does.”

Kent determined that the Rv0455c protein has an unusual “cinched” structure that could help explain its unique function in tuberculosis bacteria. The structure may also help determine whether it’s possible to target the protein with therapeutics. 

Looking ahead
The findings suggest that targeting the recycling of iron-carrying molecules may lead to the development of much-needed drugs to combat one of the world’s deadliest bacterial pathogens.

Kent is also optimistic that the findings could help augment existing treatments for tuberculosis.

“Because treatment cycles are long for tuberculosis, a common problem with is multi-drug resistance,” says Kent. “There’s a very good possibility that there will be implications for this protein in interrupting some of the processes that lead to bacterial resistance.”

Institute News

How proteins age

Authorsgammon
Date

October 19, 2015

Header image

SBP researchers and colleagues discover a mechanism that regulates the aging and abundance of secreted proteins.

Physiological processes in the body are in large part determined by the composition of secreted proteins found in the circulatory systems, including the blood. Each of the hundreds of proteins in the blood has a specific life span that determines its unique range of abundance. In fact, measurements of their quantities and activities contribute to many clinical diagnoses. However, the way in which normal protein concentrations in the blood are determined and maintained has been a mystery for decades.

Biomedical scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC Santa Barbara (UCSB) have now discovered a mechanism by which secreted proteins age and turnover at the end of their life spans. Their findings, which shed light on a crucial aspect of health and disease, appear today in the Proceedings of the National Academy of Sciences (PNAS).

“This is a fundamental advance that is broadly applicable and provides an understanding of how secreted proteins, which are involved in many important physiological processes, normally undergo molecular aging and turnover,” said senior author Jamey Marth, PhD, professor in SBP’s NCI-designated Cancer Center.

“When a secreted protein is made, it has a useful life span and then it must be degraded — the components are then basically recycled,” added Marth, also director of UCSB’s Center for Nanomedicine and a professor in the campus’s Department of Molecular, Cellular, and Developmental Biology. “We can now see how the regulation and alteration of secreted protein aging and turnover is able to change the composition of the circulatory system and thereby maintain health as well as contribute to various diseases.”

This newly discovered mechanism encompasses multiple factors, including circulating enzymes called glycosidases. These enzymes progressively remodel N-glycans, which are complex structures of monosaccharide sugars linked together and attached to virtually all secreted proteins.

It is the N-glycan structure itself that identifies the protein as nearing the end of its life span. Subsequently, multiple receptors known as lectins — carbohydrate-binding proteins — recognize these aged proteins and eliminate them from circulation.

Marth and colleagues identified more than 600 proteins in the bloodstream that exhibit molecular signs of undergoing this aging and turnover process. Many of these proteins are regulators of proteolysis (the breakdown of proteins), blood coagulation and immunity.

Honing in on individual examples, the researchers were able to track each of them through time and watch the process unfold. “In these studies we further saw that the different life spans of distinct proteins are accounted for by the different rates of aging due to N-glycan remodeling,” said lead author Won Ho Yang, PhD, a postdoctoral associate at SBP and at UCSB’s Center for Nanomedicine.

“Altering this aging and turnover mechanism is the fastest way to change the abundance of a secreted protein, which we increasingly note is occurring at the interface of health and disease,” Marth explained. “In retrospect from published literature and from studies in progress, we can now see how sepsis, diabetes and inflammatory bowel disorders can arise by the targeted acceleration or deceleration of secreted protein aging and turnover.”

“The discovery of this mechanism provides a unique window into disease origins and progression,” Marth added. “It has been known that circulating glycosidase enzyme levels are altered in diseases such as sepsis, diabetes, cancer and various inflammatory conditions. The resulting changes in the composition and function of the circulatory systems, including the blood and lymphatic systems, can now be identified and studied. We are beginning to see previously unknown molecular pathways and connections in the onset and progression of disease.”