13. A coreceptor is an enzyme courier · Prof. Kwon's TCR-HLA and CD4/CD8, First Steps

Lesson 11 left something odd standing. CD4 barely binds class II at all — and yet without CD4 a helper T cell does not respond.

The answer is not on the outside of CD4 but on the inside.

The cytoplasmic tails of CD4 and CD8α carry Lck hanging off them

Lck is a tyrosine kinase — the first button of T cell signalling. Two cysteines on the tail and two on Lck bite down together on a single zinc ion, locking like a clasp. This is called the zinc clasp.

The order things happen in

①

The TCR grips a fragment

The TCR itself has no tail to signal with. The CD3 chains alongside it do the signalling.

②

The coreceptor lands beside it

It grips the platform of the same MHC molecule, which puts Lck right next to the TCR.

③

Lck phosphorylates the CD3 tails

It adds phosphate to sites called ITAMs on the CD3 tails. There are ten of them.

④

ZAP-70 arrives and binds

It recognises phosphorylated ITAMs and docks. From here it runs on to LAT, calcium and NFAT.

Without a coreceptor, step ③ is far slower — Lck has to happen to be nearby. With one, it is already there.

Twelve-fold at a 0.3 s half-life, 1.4-fold at 5 s. It works hardest near the threshold.

Python Runs in your browser

# A toy model — with and without the coreceptor
import thla

print(f"{'half-life':>11}{'no coreceptor':>16}{'with':>10}{'ratio':>9}")
for t in [0.3, 0.5, 1.0, 2.0, 5.0]:
    a = thla.proofread(t, steps=4)
    b = thla.proofread(thla.with_coreceptor(t, boost=3.0), steps=4)
    print(f"{t:>11.1f}{a:>16.4f}{b:>10.4f}{b/a:>9.1f}")
print()
print("The weaker the fragment, the more the coreceptor matters.")

Bring Lck in or take it away. The weak fragments collapse first.

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CD4 brings more Lck than CD8 does

Both use the zinc clasp. But CD4 is far more efficient at it: a substantial share of CD4 molecules carry Lck, while the fraction is lower for CD8.

The difference sounds trivial and its consequences are not. The fate decision in lesson 14 rides on exactly this asymmetry.

The numbers are rough figures from the literature. What matters is the ordering, not the decimals.

Python Runs in your browser

# Why size is the issue — the gap between cells and the height of molecules
import thla

gap = 15
print(f"gap between the membranes once TCR-pMHC engages : about {gap} nm")
print()
for name, h in [("TCR + pMHC", 14), ("CD8 + MHC-I", 14), ("CD45 (short form)", 22),
                ("CD45 (long form)", 40), ("CD43", 45)]:
    fit = "fits" if h <= gap + 1 else "pushed out"
    print(f"   {name:<20}{h:>4} nm   {fit}")

🤔 Check yourself

What hangs off the cytoplasmic tails of CD4 and CD8?

🤔 Check yourself

When does a coreceptor's help matter most?

🤔 Check yourself

What does kinetic segregation say?