The Rossmann fold is a fundamental structural motif found within proteins, representing a specific arrangement of secondary structures. It is notable for its consistent role in binding nucleotides, which are molecules that play diverse roles in biological processes. Its prevalence across various proteins highlights its significance in cellular machinery and provides insight into the architecture and function of many biological molecules.
Understanding the Rossmann Fold’s Structure
The Rossmann fold is characterized by its distinctive arrangement of alternating beta-strands and alpha-helices. This pattern appears as a β-α-β-α-β motif, where parallel beta-strands (β) are connected by alpha-helices (α). The classical Rossmann fold contains six parallel beta strands, though related “Rossmann-like” folds may have five.
These beta-strands are hydrogen-bonded, forming an extended beta-sheet core. Alpha-helices surround both sides of this beta-sheet, creating a three-layered “sandwich” architecture. A defining feature is a specific crossover between beta-strands, often between the third and fourth in the classical version, which forms a pocket for nucleotide cofactors.
The Rossmann Fold’s Role in Biology
The Rossmann fold’s primary function in enzymes is to bind nucleotide cofactors like nicotinamide adenine dinucleotide (NAD+), flavin adenine dinucleotide (FAD), adenosine triphosphate (ATP), and guanosine triphosphate (GTP). These nucleotides often contribute to substrate binding.
A characteristic element is the glycine-rich loop, located between the first beta-strand and alpha-helix. This tight turn allows the polypeptide backbone to bend sharply, positioning the loop to interact with the phosphate groups of the bound nucleotide. This arrangement helps manipulate the nucleotide’s phosphate group, supporting the enzyme’s catalytic activity.
Proteins with the Rossmann fold participate in various biological reactions. Their cofactor binding enables roles in metabolism, including oxidation-reduction reactions where NAD+ and FAD act as electron carriers. They also function in energy transfer and signal transduction pathways, highlighting the diverse biological roles facilitated by this common structural motif.
Proteins Featuring the Rossmann Fold
The Rossmann fold is present in diverse protein and enzyme families, showcasing its versatility in biological systems. Dehydrogenases, for example, frequently contain this fold, requiring cofactors like NAD+ or NADP+ to catalyze oxidation-reduction reactions, such as in glycolysis or the Krebs cycle. These enzymes facilitate the transfer of hydrogen atoms or electrons between molecules, which is fundamental to energy metabolism.
Kinases also commonly feature the Rossmann fold, utilizing it to bind ATP for transferring phosphate groups to target molecules. This phosphorylation is a common mechanism in cellular signaling and regulation, influencing protein activity and metabolic pathways. Reductases employ the Rossmann fold to bind nucleotide cofactors, enabling them to reduce substrates by adding electrons or hydrogen atoms.
Other examples include enzymes involved in nucleic acid metabolism, such as some ribonucleases, which contribute to the processing and degradation of RNA. The widespread presence of the Rossmann fold in these varied enzyme families underscores its adaptability and efficiency in facilitating diverse biochemical reactions across different biological processes. More than 20% of all known protein structures contain Rossmann-like domains, highlighting their prevalence.
Evolutionary Insights from the Rossmann Fold
The widespread prevalence of the Rossmann fold across different organisms and numerous protein families strongly suggests its ancient evolutionary origin. This fold is considered one of the most prevalent and diversified “doubly-wound superfolds.” Its presence in a vast array of metabolic enzymes indicates that it likely arose at early stages of protein evolution, preceding the Last Universal Common Ancestor (LUCA), from a primordial nucleotide-binding domain.
The consistent structure of the Rossmann fold, despite significant variations in amino acid sequences among different proteins, points to its functional efficiency and utility. This structural conservation implies that the fold either diverged frequently from a common ancestor to adopt new functions or emerged independently multiple times through convergent evolution. The high degree of three-dimensional structure conservation, compared to sequence conservation, supports the idea that this fold is a highly effective and evolutionarily successful structural unit.