What's the largest protein?

PKZILLA-1, discovered in 2024, is the largest known protein at 4.7 megadaltons with 45,212 amino acids

Dr. Matic Broz
Dr. Matic Broz
Computational chemist
What's the largest protein?

What is the largest protein?

The largest known protein is PKZILLA-1, a giant enzyme discovered in August 2024 by scientists at UC San Diego's Scripps Institution of Oceanography. This massive protein reaches a record-breaking mass of 4.7 megadaltons and contains 45,212 amino acids arranged into 140 enzyme domains.

PKZILLA-1 was found in the golden algae Prymnesium parvum, where it functions as a polyketide synthase enzyme responsible for producing prymnesin—a potent toxin that causes massive fish kills during harmful algal blooms.

"This is the Mount Everest of proteins," noted Bradley Moore, the study's senior author, emphasizing how this finding expands our understanding of biological possibility.

FeaturePKZILLA-1Titin (previous record)
Mass4.7 megadaltons3.7–3.8 megadaltons
Amino acids45,21234,350
Enzyme domains140N/A (structural)
FunctionToxin synthesisMuscle elasticity
OrganismPrymnesium parvum (algae)Human muscle
Discovery20241979

What about titin?

Until 2024, titin (also called connectin) held the record as the largest known protein. Found in human muscle tissue, titin consists of 34,350 amino acids in its canonical isoform and weighs approximately 3.7 to 3.8 megadaltons. The protein stretches over 1 micrometer in length, which is about 100 times larger than a typical protein.

Titin functions as a molecular spring in muscle cells, spanning from the Z-disk to the M-line of the sarcomere. It provides passive elasticity that allows muscles to stretch and return to their resting state. Remarkably, titin constitutes about 10% of muscle mass, making it the third most abundant protein in muscle after actin and myosin.

The mouse homologue of titin is even larger, comprising 35,213 amino acids with a molecular weight of approximately 3.9 megadaltons.

How big is PKZILLA-1 compared to typical proteins?

To appreciate just how massive PKZILLA-1 is, consider that a typical protein contains 300–500 amino acids and weighs approximately 33–55 kilodaltons (kDa). PKZILLA-1, at 4.7 megadaltons, is roughly 100 times larger than an average protein.

Protein categoryAmino acidsMolecular weight
Typical protein300–50033–55 kDa
Large protein1,000–5,000100–500 kDa
Giant protein (titin)34,3503,700–3,800 kDa
Largest protein (PKZILLA-1)45,2124,700 kDa

PKZILLA-1 reaches approximately 1 micrometer in length or about 0.0001 centimeters or 0.00004 inches. Despite its enormous size, it remains far smaller than most cells; a typical human cell is 10–100 micrometers in diameter.

What does PKZILLA-1 do?

PKZILLA-1 and its slightly smaller companion PKZILLA-2 (3.2 megadaltons, 99 enzyme domains) work together to produce prymnesin, the algae's toxic compound. These giant enzymes catalyze an astounding 239 chemical reactions in sequence to assemble the complex toxin molecule.

This discovery has practical implications:

  1. Algal bloom monitoring: Detecting PKZILLA genes in water samples could enable early warning systems for toxic algal blooms, potentially preventing fish kills before they occur.
  2. Pharmaceutical applications: Understanding how nature assembles such complex molecules could help scientists synthesize new compounds for medical or industrial applications. As Moore noted, "Understanding how nature has evolved its chemical wizardry gives us as scientific practitioners the ability to apply those insights to creating useful products, whether it's a new anti-cancer drug or a new fabric."

What are the top 10 largest proteins?

Based on molecular weight, here are the largest known proteins:

RankProteinMolecular weightAmino acidsFunction
1PKZILLA-14,700 kDa45,212Toxin synthesis in algae
2Titin3,000–3,800 kDa27,000–34,350Muscle elasticity
3PKZILLA-23,200 kDa~30,000Toxin synthesis in algae
4Versican~1,000 kDaVariableExtracellular matrix
5Obscurin720–900 kDa~7,000Muscle organization
6Nebulin600–900 kDa~6,700Thin filament regulation
7AHNAK~700 kDa~5,890Membrane organization
8Ryanodine receptor (RyR1)~565 kDa~5,000Calcium release channel
9Apolipoprotein B-100~550 kDa4,536Lipid transport
10Plectin~500 kDa~4,680Cytoskeletal crosslinking

Notably, many of the largest proteins are found in muscle tissue (titin, obscurin, nebulin, dystrophin), reflecting the complex structural requirements of the contractile apparatus.

Why are some proteins so large?

Giant proteins serve specialized functions that require their extraordinary size:

  • Structural scaffolding: Titin spans the entire length of the muscle sarcomere (~1 μm), physically connecting the Z-disk to the M-line. This requires a protein large enough to bridge this distance while maintaining elastic properties.
  • Multi-step enzymatic assembly: PKZILLA-1 contains 140 enzyme domains that work in sequence. Rather than relying on 140 separate enzymes finding each other through diffusion, consolidating them into a single protein ensures efficient, sequential processing of chemical reactions.
  • Mechanical stability: Large muscle proteins like titin, nebulin, and obscurin provide mechanical stability to the contractile apparatus, acting as molecular rulers and scaffolds that organize other proteins.

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