Abstract
Amyloid precursor protein (APP) family members are involved in essential neuronal development including neurite outgrowth, neuronal migration and maturation of synapse and neuromuscular junction. Among the APP gene family members, amyloid precursor-like protein 1 (APLP1) is selectively expressed in neurons and has specialized functions during synaptogenesis. Although a potential role for APLP1 in neuronal evolution has been indicated, its precise evolutionary and functional contributions are unknown. This study shows the molecular evolution of the vertebrate APP family based on phylogenetic analysis, while contrasting the evolutionary differences within the APP family. Phylogenetic analysis showed 15 times higher substitution rate that is driven by positive selection at the stem branch of the mammalian APLP1, resulting in dissimilar protein sequences compared to APP/APLP2. Docking simulation identified one positively selected site in APLP1 that alters the heparin-binding site, which could affect its function, and dimerization rate. Furthermore, the evolutionary rate covariation between the mammalian APP family and synaptic adhesion molecules (SAMs) was confirmed, indicating that only APLP1 has evolved to gain synaptic adhesion property. Overall, our results suggest that the enhanced synaptogenesis property of APLP1 as one of the SAMs may have played a role in mammalian brain evolution.
Highlights
Amyloid precursor protein (APP) family comprises of type-I single-pass transmembrane proteins and is composed of APP, amyloid precursor-like protein (APLP) 1, and APLP2
APP family was detected in class of mammal, bird, reptile, amphibian, and fish, while amyloid precursor-like protein 1 (APLP1) was not found in birds[2]
The branching order of mammal, bird, reptile, amphibian, and fish is irregular for APLP1, though APP and APLP2 branching were based on the species tree
Summary
Amyloid precursor protein (APP) family comprises of type-I single-pass transmembrane proteins and is composed of APP, amyloid precursor-like protein (APLP) 1, and APLP2. The physiological function of APLP1 is modified; compared with APP and APLP2, APLP1 has an augmented synaptogenic function This function had been demonstrated through the co-culture of neurons and non-neuronal HEK293T cells overexpressing APP family members. Among the APP family members, APLP1 exhibited the most efficient induction of s ynapses[3,4,15] Based on this function, the APP family is classified as a synaptic adhesion molecule (SAM), fulfilling synaptic localization/ function and cell adhesion property observed in proteins such as neuroligin and neurexin. Significant evolution in APLP1 occurs at the stem of the mammalian APLP1, changing its protein properties, including a heparin-binding site for dimerization, distinct from that in the vertebrate APP family. The function of APLP1 as SAMs perhaps played a role in mammalian brain evolution
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