Over the past century, scientists have developed and deployed amazing technologies such as X-ray crystallography and cryo-electron microscopy to determine protein structure, and thereby answered countless important questions. But new work shows that understanding protein structure can sometimes be more complicated than we think.

A group of researchers from Lawrence Berkeley National Laboratory (Berkeley Lab) studying the world's most abundant protein, an enzyme involved in photosynthesis called rubisco, showed how evolution can lead to a surprising diversity of molecular assemblies that all accomplish the same task. The findings, published today in Science Advances, reveal the possibility that many of the proteins we thought we knew actually exist in other, unknown shapes.

Historically, if scientists solved a structure and determined that a protein was dimeric (composed of two units), for example, they might assume that similar proteins also existed in a dimeric form. But small sample size and sampling bias—unavoidable factors given that it's very difficult to convert naturally liquid proteins into solid, crystallized forms that can be examined via X-ray crystallography –were obscuring reality.

"It's like if you walked outside and saw someone walking their dog, if you had never seen a dog before then saw a wiener dog, you'd think, 'OK, this is what all dogs look like.' But what you need to do is go to the dog park and see all the dog diversity that's there," said lead author Patrick Shih, a faculty scientist in the Biosciences Area and Director of Plant Biosystems Design at the Joint BioEnergy Institute (JBEI). "One takeaway from this paper that goes beyond rubisco, to all proteins, is the question of whether or not we are seeing the true range of structures in nature, or are these biases making it seem like everything looks like a wiener dog."