California mussels Mytilus californianus owe their tenacity to a holdfast known as the byssus, a fibrous extracellular structure that ends distally in flattened adhesive plaques. The "footprints" of freshly secreted plaques deposited onto glass coverslips were shown by matrix-assisted laser desorption ionization time of flight mass spectrometry to consist chiefly of proteins ranging in mass from 5200 to 6700 Da. These proteins, variants of a family known as mcfp3 (M. californianus foot protein 3), were purified from acetic acid/urea extracts of plaques and foot tissue. Mcfp3 appears to sort into fast and slow electrophoretic variants. Both are rich in Gly and Asn and exhibit post-translational hydroxylation of Tyr and Arg to Dopa and 4-hydroxyarginine, respectively, with the fast variant containing more than twice as much Lys ؉ Arg. Both the slow and fast variants were partially sequenced from the N terminus, and the complete sequences of 12 variants were deduced from cDNA using degenerate oligonucleotides, PCR, and rapid amplification of cDNA ends. Mcfp3s are highly polar molecules and contain up to 28 mol % Dopa, which remains intact and may be crucial for adhesion to metal and mineral surfaces.The fabrication of strong and durable adhesive bonds between macromolecules and metal or mineral surfaces in a wet environment is one of the most persistent challenges for modern adhesive technology (1). Ironically, this is "business as usual" for the marine mussels who inhabit rocky wind-swept seashores. Mussels (Mytilus) thrive despite persistent surf and tides thanks in part to a robust holdfast structure called the byssus, which consists of a bundle of threads each of which is tipped distally by an adhesive plaque that bonds to mineral and metal surfaces. The adhesive strategies of mussels and other sessile marine invertebrates are increasingly envisioned as paradigms for designing tough water-resistant adhesives (2, 3).How is water a problem for adhesion? There are many complicating factors, but one of the most fundamental involves the dielectric constant of water. Most known cases of practical and biological adhesion are mediated by noncovalent interactions between the adhesive and the adherend surface. The interaction energy of a charge-charge interaction, for example, is governed by Coulomb's law aswhere Q 1 and Q 2 are the charges on two interacting molecules, ⑀ is the dielectric constant of the medium, and r is the interatomic distance (4). The dielectric constant of water (⑀ ϭ 80) is much higher than that of vacuum (⑀ ϭ 1) or nonpolar solvents (⑀ ϭ 2-3), and this, consequently, greatly diminishes the magnitude of interaction energies that are possible in water. Ligand-receptor adhesion typically gets around this limitation by conformation-dependent protein-ligand interactions, in which ligand binding usually occurs within hydrophobic protein pockets having a much lower dielectric constant than the surrounding bulk water (5). The extent to which mussels can exploit this approach in byssal adhesion seems limite...

Tangye and collaborators use a series of mutants to elucidate the pathways required to generate distinct subsets of human effector CD4+ T cells.

SUMMARY Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels, and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.