Mature evolutionarily conserved cathelicidin is a biologically inactive protein of ~19Da. It is processed by serine proteases into a 94 amino acid cathelin prosequence and an antimicrobial peptide (AMP) of 37 amino acids (see Figure 1). This peptide is further processed by serine proteases to generate a family of four unrelated peptides (19, 27, 39, or 31 amino acids), each of which has a selective AMP activity against viruses, bacteria, or fungi.
Fig1. Illustration of the gene product cathelicidin that is processed by proteinase-3 (a serine protease) to yield a signal peptide (~30 amino acids, brown color) a cathelin prosequence (of 94 amino acids, green color) and a 37 amino acid antimicrobial protein (LL-37, blue color). Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain. LL-37 begins its amino acid chain with two leucines. Exposure of the 37 amino acid AMP to other serine proteases (e.g., from skin at sites of inflammation) results (in this example) in the generation of four unique peptides, with 31, 30, 27, and 19 amino acids, respectively. Each of these peptides will have a different profile of biological actions. AMPs have the ability to participate in diverse functions such as wound healing, chemotaxis, and antiogenesis. The basic mode of action of an AMP is described in Figure 2. Modified from R.L. Gallo et al. J. Am. Acad. Dermatol. 52: 381 (2005).
Fig2. A schematic wheel plot of a 37 amino acid cathelicidin’s distribution of positively charged and hydrophobic residues. The cathelicidin family in humans is restricted to a single gene, CAMP, with the resulting AMP protein product often referred to as hCAP18/LL-37. The α-helix of the AMP has a hydrophobic surface on one side and a hydrophilic positively charged surface on the opposite side. The schematic wheel of the figure traces the amino acid sequence of the LL-37 amino acid peptide. The black color circles map the hydrophobic amino acids (leucine, isoleucine, phyenylalanine, and valine). The white color circles denote positively charged (arginine, histidine, and lysine) and blue spheres denote negatively charged (aspartic and glutamic) or amino acids. In the host individual that is experiencing a microbial infection, as a consequence of the activation of the innate immune response, the LL-37 peptide/cathelicidin becomes inserted into the plasma membrane of the invading microbe, which changes the membrane permeability and causes a decrease in protein biosynthesis that ultimately leads to the death of that microbe. Modified from R.L. Gallo et al. J. Am. Acad. Dermatol. 52: 381 (2005).
The structural basis for the mechanism of the antimicrobial activity of a small cathelicidin derived pep tide is illustrated by the wheel plot of the peptide’s amino acid residues (see Figure 2). Each peptide is organized into α-helical structure such that the amino acids found on one side are positively charged, while the amino acids on the opposite side are hydrophobic. This evolutionarily created structure enables the positively charged surface of the peptide to interact with negatively charged cell membranes followed by entry of the peptide into the hydrophobic phase of the cell membrane to create a voltage-dependent ion channel. This results in a change of the cell membrane’s permeability, leading to interference of the cytoplasmic process that ultimately causes lysis of the target cell, leading to a lethal outcome.
