Proteins were originally described in the early eighteenth century by the Dutch chemist Mulder¹ and the Swedish chemist Berzelius.² Mulder was the first person to ascertain the chemical composition of proteins and he observed that all proteins had the same empirical formula. At the time, his colleague Berzelius was the first to distinguish between organic and inorganic compounds. Berzelius proposed the name “protein” for Mulder’s new findings and Mulder, in fact, used this terminology in his first publication.

Later, the German chemist and physiologist von Voit³ stated that protein is the most important nutrient in the structure of the body. Voit was considered by many to be the father of modern dietetics. The enzymatic role of proteins was first discovered in the nineteenth century by Sumner,⁴ who showed that the enzyme urease is a protein. Some years later, the first protein sequence, that of insulin, was presented by Sanger,⁵ who won the Nobel Prize for this achievement in 1958. In the same year, the molecular structures of the proteins hemoglobin and myoglobin were discovered by Max Perutz⁶ and Kendrew.⁷

Emil Fischer⁸ (Fig. 16.1) proposed that enzymes had particular shapes into which substrates fit exactly. He first postulated in 1894 this specific action of an enzyme with a single substrate.

This model of exact fit is referred to as the “lock and key” model because an enzyme’s binding to a substrate is analogous to the specific fit of a key into a lock (Fig. 16.2).

The primary structure refers to the linear arrangement of amino acids (Fig. 16.3).

The sequence of amino acids determines the function of the protein. Variations in the amino acid sequence may occur physiologically, such as in polymorphism, which occurs when two or more clearly different phenotypes exist in the same population of a species – in other words, more than one form or “morph” occurs. Polymorphism allows for diversity within a population. A common example is the different allelic forms that give rise to different blood groups in humans.

However, variations in the amino acid sequence may also occur in the form of mutations. Mutations can result in several different types of changes in the amino acid sequence. These can have no effect or they may prevent the protein from functioning properly at all. Retinitis pigmentosa (Fig. 16.4) is one example of a genetic group of eye disorders that results from mutations. Multiple genes are known that, when mutated, can cause the retinitis pigmentosa phenotype. In 1989, a mutation was identified in the gene for rhodopsin (Sect. 16.5.4). Since then, more than 100 other mutations leading to RP have been found.

Corneal dystrophies are another example of eye disorders resulting from mutations. Some corneal dystrophies may be asymptomatic, whereas others may cause significant vision impairment. An example is type 1 lattice dystrophy, one of the most common inherited corneal dystrophies, which is characterized by the accumulation of amyloid throughout the middle and anterior stroma. Type I lattice dystrophy is an autosomal dominant disorder that results from mutations in the TGFBI gene (5q31). The TGFB1 gene was first discovered in 1997 by Munier et al. in Lausanne, Switzerland. This gene encodes a member of the transforming growth factor beta (TGFB) family of cytokines, which are multifunctional peptides that regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. Many cells have TGFB receptors and the protein positively and negatively regulates many other growth factors. Mutations in the TGFB-1 gene can lead to various pathologies, including corneal dystrophies (Fig. 16.5).

Another example of a disorder resulting from mutations is galactosemia. Several types of galactosemias are recognized, each of which is caused by mutations in a particular gene and affect different enzymes involved in breaking down the sugar galactose. Infants with galactosemia who are not treated promptly with a low-galactose diet face complications. Affected children are also at increased risk of delayed development, speech difficulties, and intellectual disability, as well as the development of lens cataracts.

Lens dislocations that occur in the context of Marfan syndrome (Fig. 16.6) are often due to a mutation in the fibrillin-1 molecule. Fibrillin-1 is an extracellular matrix glycoprotein protein that is the main component of the microfibrils. Multiple autosomal dominant mutations in FBN1 have been described for a wide spectrum of disease, including complete and incomplete forms of Marfan syndrome.

The secondary structure describes the folding of the polypeptide backbone of the protein (Fig. 16.3). Two main types of secondary structures are recognized: the alpha helix and the beta sheet. The alpha helix takes the form of a spiral structure consisting of a tightly packed, coiled polypeptide backbone core with the side chains of the amino acids extending outward from the central axis. The keratins, for example, are a family of fibrous proteins whose structure is nearly entirely alpha-helical. The beta sheet is another secondary structure in which all of the peptide bond components are involved in hydrogen bonding. The surfaces of these beta sheets appear to be “pleated,” which is why they are often called “beta-pleated sheets.”

The third type of structure found in proteins is called the tertiary structure (Fig. 16.3). The tertiary structure is the final specific geometric shape that a protein assumes. This final shape is determined by a variety of bonding interactions between the side chains on the amino acids. These types of bonding interactions include hydrogen bonding, salt bridges, bisulfate bonds, and nonpolar hydrophobic interactions. Disulfide bonds, for example, occur between the sulfurs of two cysteine side chains. An example of a protein with many disulfide linkages between cysteines is found physiologically in the lens zonules. Therefore, a cysteine deficiency may affect normal zonular development (the zonules become brittle and can break), leading to lens dislocation.

The quaternary structure of a protein is a larger assembly of several protein molecules or ­polypeptide chains. As in the tertiary structure, the quaternary structure is stabilized by noncovalent interactions (e.g., hydrogen bonds or ionic bonds). Complexes of two or more polypeptides are called multimers (e.g., a protein is a tetramer if it contains four subunits). These subunits may either function independently of each other or work cooperatively, as in the case of hemoglobin, where the binding of oxygen to one subunit of the tetramer increases the affinity of the other subunits for oxygen (Fig. 16.7).

All proteins are synthesized from only twenty naturally occurring amino acids, which belong to the group of α-amino acids (one carbon, the α-carbon, has all of the remaining groups attached to it). These groups include an amino group, a carboxyl (acidic) group, hydrogen, and one of twenty different R groups (side chains) that give each amino acid type its specific properties. Proteins are polypeptides; i.e., they are single linear chains of amino acids bonded together by peptide bonds (Fig. 16.8).

We shall first discuss the role of proteins in general and then in the eye.

Proteins are the most common and manifold macromolecules in living cells. They are found in all cells. One single cell contains thousands of different proteins whose biological functions may differ greatly from each other. Proteins occur also outside the cells. The proteins in the blood, for example, serve as protectors (e.g., in the form of antibodies) or as long-distance haulers of molecules such as oxygen (e.g., hemoglobin). Some proteins function as structural proteins that confer stiffness and rigidity to otherwise-fluid ­biological components. Other proteins, such as signaling proteins, form a part of the communications network of our nervous system. Certain proteins can also function as “chaperones” and assist in the folding, unfolding, and assembly of other proteins. The central role of all proteins, however – as we will show later – is their role as the most important end-products of information flow between and within cells. In a certain sense, proteins are the molecular instruments through which genetic information is expressed.

When a protein must be available at short notice or in large quantities, it is produced in its inactive form, called a pro-protein (e.g., proinsulin). This inactive form of the protein consists of a long chain of amino acids as well as one or more inhibitory peptides that can be activated when the inhibitory sequence is removed. This long chain of amino acids directs the transport of proteins to their specific location (e.g., insertion into membranes, as in the case of secretory proteins). A part of this long chain of amino acids, thus, acts as an “address.” Once the protein has arrived at the specific location, these sequences of amino acids can be removed or processed. Further splicing can activate the protein.

The activity of other proteins and of enzymes in particular can be regulated by the addition or removal of phosphate groups. Protein phosphorylation (the addition of a phosphate group) is recognized as one of the primary ways in which cellular processes are regulated. Phosphorylation reactions are catalyzed by a family of enzymes called protein kinases that utilize ATP as a phosphate donor (Fig. 16.9).

Phosphate groups are removed from phosphorylated enzymes by the action of phosphoprotein phosphatases. Depending on the specific enzyme, the phosphorylated form may be more or less active than the unphosphorylated enzyme. The discovery of reversible protein phosphorylation was made by the biochemists Fischer and Krebs⁹ (Fig. 16.10).

Proteins can be grossly classified into those with functional and those with structural properties. We will not focus on the classification of proteins in any further detail but will, instead, concentrate on proteins that play a special role in the eye.

The overall role of proteins in the eye is principally the same as in all other tissues in the body. However, there are a few peculiarities.