Blood Protein Puzzle Solved: New Method Uncovers Hidden Players

Scientists pinpoint elusive molecules critical for health

Researchers have devised a novel strategy to identify rare blood proteins, akin to finding a specific character in an endless “Where’s Waldo?” collection. This breakthrough offers new insights into how these proteins influence health and disease.

Decoding the Blood’s Complex Proteome

The human bloodstream contains over a thousand distinct glycoproteins, with just ten accounting for 90% of the total mass. This vast disparity, known as dynamic range, complicates the detection of less abundant proteins and their corresponding receptors.

A team from Sanford Burnham Prebys, collaborating with Scripps Research Institute, has published groundbreaking findings in Nature Communications. Their research details a method for isolating proteins that interact with endocytic lectins, specifically the mannose receptor Mrc1 (also known as CD206).

A Signal Boost for Discovery

To navigate the immense variations in protein concentrations, the scientists utilized Concanavalin A (ConA), a mannose-binding lectin. This approach effectively amplified the signal from low-abundance proteins, enabling the identification of hundreds of Mrc1 binding partners.

“ConA and Mrc1 both possess similar mannose linkage binding capabilities, but Mrc1 is not readily available as a comparable active recombinant protein,” explained **Mayank Saraswat**, PhD, a senior staff scientist at Sanford Burnham Prebys and co-lead author. This limitation necessitated an indirect approach.

The researchers isolated proteins binding to ConA from both normal mice and mice lacking Mrc1. “Comparisons revealed increased sensitivity and selectivity, allowing for the identification of the receptor’s ligands as they accumulate in the blood in the absence of Mrc1,” **Saraswat** added.

Mrc1’s Crucial Role in Blood Regulation

Mrc1 plays a vital role in maintaining healthy levels of numerous plasma proteins by binding to mannosylated proteins. This interaction triggers an endocytic clearance mechanism, limiting the lifespan and quantity of these ligands in circulation.

By comparing protein levels in normal mice and those lacking Mrc1, the team observed a doubling or more of 244 mannosylated blood plasma proteins. This accumulation was attributed to Mrc1’s absence, which failed to keep these protein levels in check.

Unveiling Protein Functions and Health Implications

Further analysis of the newly identified ligands using bioinformatics revealed their significant biological roles. Many of these proteins are crucial for bodily functions.

“We noticed that a lot of the proteins had very important roles to play. Renin and angiotensin converting enzyme, for example, are major regulators of blood pressure.”

—Jamey Marth, PhD, Professor at Sanford Burnham Prebys

The scientists focused on eight of these proteins known to impact blood pressure, inflammation, organ function, and sepsis. Their findings suggest a direct link between the accumulation of these mannosylated proteins and disruptions in normal physiology.

In a critical observation regarding sepsis, mice genetically modified to lack Mrc1 exhibited a faster mortality rate from the condition. This highlights the receptor’s protective role.

“When we looked at samples of blood from human sepsis patients, we found that there was a difference in the proteins that were accumulating when compared to the Mrc1-deficient mice,” stated **Saraswat**. “However, when we compared the pathways controlled by these proteins, half of those activated in human sepsis were also activated by Mrc-1 dysfunction.”

The research underscores the need to understand how glycosidic linkages influence the abundance and activity of blood glycoproteins, and how these modifications affect physiological functions. According to the World Health Organization, sepsis affects millions of people globally each year, with a significant mortality rate, emphasizing the importance of this research (WHO, 2024).

Future Directions in Glycoprotein Research

This work opens new avenues for understanding complex biological systems and developing targeted therapies for diseases linked to protein dysregulation.

Reference: Restagno D, Saraswat M, Aziz PV, et al. Mrc1 (MMR, CD206) controls the blood proteome in reducing inflammation, age-associated organ dysfunction and mortality in sepsis. Nat Commun. 2025;16(1):6267. doi:10.1038/s41467-025-61346-4