How a Single Protein Holds the Key to Cellular Invasion
By identifying specific amino acid residues on the Hemagglutinin protein, scientists have unlocked how measles targets different cell receptors
Imagine a skilled thief who can pick two very different locks. For decades, scientists knew the measles virus was just such a master infiltrator, capable of breaking into our cells using two different "doors"—proteins on our cell surfaces called SLAM and CD46.
But how does one virus have two different keys? The answer lies in a single, crucial viral protein, Hemagglutinin (H), which acts as the virus's master key. Recent research has cracked this code, identifying the precise tumblers in the lock—the specific amino acid residues on the H protein—that allow measles to open either the SLAM or CD46 door.
This discovery, visualized on a new and improved 3D model of the H protein, is a monumental leap in virology. It not only solves a long-standing mystery but also opens up new avenues for creating smarter, safer vaccines and powerful new cancer-fighting therapies .
The Hemagglutinin (H) protein acts as the virus's master key to unlock cellular entry.
Measles can enter cells through two different receptors: SLAM and CD46.
To understand the virus's trick, we first need to understand the doors it opens.
Signaling Lymphocyte Activation Molecule
This door is found primarily on cells of our immune system, like lymphocytes. This is why measles is so effective at causing immunosuppression—it directly attacks the very cells that are supposed to defend us .
Complement Regulatory Protein
This door is ubiquitously present on all nucleated cells in the human body, acting as a "self" marker to protect our cells from our own immune system. The vaccine strains of the measles virus have evolved to preferentially use this door .
The Hemagglutinin (H) protein on the virus's surface is the "key" that fits into these cellular "locks." Binding to the lock triggers a process that forces the cell and virus to fuse, allowing the viral genetic material to invade .
3D Structural Model of Hemagglutinin Protein
Binding sites for SLAM and CD46 highlightedThe puzzle was straightforward but baffling: How can one key—the H protein—open two completely different locks?
Scientists hypothesized that different parts of the H protein must be responsible for binding to SLAM versus CD46. Proving this meant finding the exact spots and understanding how they work .
How can a single protein recognize and bind to two structurally different cellular receptors?
To identify the precise residues on the H protein that control its ability to bind to SLAM or CD46, researchers employed a powerful technique known as site-directed mutagenesis.
Think of it as genetic sculpting—precisely chiseling away at or altering individual amino acids in the H protein to see how it changes the key's function .
The experiment was elegant in its design:
Scientists started with a well-understood measles vaccine strain (known to use CD46 efficiently) and a "reporter" system. This system was designed to light up (e.g., through fluorescence) only when a successful virus-cell fusion event occurred.
Using the new 3D structural model of the H protein, they identified specific amino acid residues located in regions predicted to interact with cell receptors.
Using site-directed mutagenesis, they created a series of mutant viruses. Each mutant had one or more of the suspect amino acids changed to a different one.
The team exposed these mutant viruses to two different types of cells in the lab:
They measured the fusion activity—how effectively the virus fused with each cell type—by monitoring the "reporter" signal. High signal meant successful fusion; low or no signal meant the virus was "blind" to that particular receptor .
The results were clear and dramatic. Specific mutations completely abolished the virus's ability to use one receptor, while leaving its ability to use the other intact.
Mutations at residues like Y481 and S548 drastically reduced or eliminated fusion via the SLAM receptor, but had little to no effect on CD46-mediated fusion.
Mutations at a different set of residues, including F431 and I464, had the opposite effect, crippling CD46 usage while sparing SLAM function.
This proved conclusively that the H protein has distinct, non-overlapping binding sites for its two cellular doors. The key has two different cutting edges for two different locks .
| Amino Acid Residue | SLAM Fusion | CD46 Fusion | Conclusion |
|---|---|---|---|
| Y481 (Tyrosine) | None | Normal | Critical for SLAM |
| S548 (Serine) | None | Normal | Critical for SLAM |
| F431 (Phenylalanine) | Normal | None | Critical for CD46 |
| I464 (Isoleucine) | Normal | Reduced | Important for CD46 |
| Wild-Type (No Mutation) | Normal | Normal | Can use both receptors |
| Residue | Location on H Protein | Functional Role |
|---|---|---|
| Y481 | SLAM-binding pocket | Forms a direct contact point with the SLAM receptor |
| S548 | SLAM-binding pocket | Stabilizes the interaction with SLAM |
| F431 | CD46-binding pocket | A key hydrophobic contact for CD46 binding |
| I464 | CD46-binding pocket | Helps shape the pocket that CD46 fits into |
| Research Tool | Function in a Nutshell |
|---|---|
| Site-Directed Mutagenesis | The "genetic sculpting" tool. Allows scientists to make precise, pre-determined changes to the virus's genetic code (DNA) to alter specific amino acids in a protein. |
| Cell Lines Expressing Single Receptors | Engineered "indicator" cells. These are standardized lab cells modified to express only SLAM or only CD46, allowing for clean, unambiguous testing of receptor usage. |
| Quantitative Fusion Assay | The "scoring system." A method to objectively measure and quantify how much fusion occurs between a virus and a cell, often using fluorescent or luminescent reporters. |
| Structural Modeling (Bioinformatics) | The "3D blueprint." Using computer software and known protein structures to predict and visualize the 3D shape of the measles H protein, showing how its parts fit together. |
By identifying the specific amino acids that control SLAM and CD46 recognition, and locating them on a detailed structural map, scientists have fundamentally changed our understanding of the measles virus.
We now see it not as a mysterious entity, but as a precise piece of molecular machinery .
A vaccine virus engineered to be blind to SLAM could be even safer, as it would be less able to target immune cells.
We could engineer a measles virus that is blind to CD46 but retains its ability to enter via a receptor found only on certain cancer cells, creating a "smart virus" that specifically destroys tumors.
In unlocking the secrets of how measles unlocks our cells, we have found the key to a new frontier in medicine .