Gigantopithecus blacki was a giant hominid that inhabited densely forested environments of Southeast Asia during the Pleistocene 1. Its evolutionary relationships to other great ape species, and their divergence during the Middle and Late Miocene (16-5.3 Mya), remains disputed 2,3. Hypotheses regarding relationships between Gigantopithecus and extinct and extant hominids are difficult to substantiate because of its highly derived dentognathic morphology and the absence of cranial and post-cranial remains 1,3-6. Therefore, proposed hypotheses on the phylogenetic position of Gigantopithecus among hominids have been wide-ranging, but none have received independent molecular validation. We retrieved dental enamel proteome sequences from a 1.9 million years (Mya) old Gigantopithecus blacki molar found in Chuifeng Cave, China 7,8. The thermal age of these protein sequences is approximately five times older than any previously published mammalian proteome or genome. We demonstrate that Gigantopithecus is a sister clade to orangutans (genus Pongo) with a common ancestor about 10-12 Mya, implying that the Gigantopithecus divergence from Pongo is part of the Miocene radiation of great apes. Additionally, we hypothesize that the expression of alpha-2-HS-glycoprotein (AHSG), which has not been observed in enamel proteomes previously, had a role in the biomineralization of the thick enamel crowns that characterize the large molars in the genus 9,10. The survival of an Early Pleistocene dental enamel proteome in the subtropics further expands the scope of palaeoproteomic analysis into geographic areas and time periods previously considered incompatible with genetic preservation. Gigantopithecus blacki is an extinct, potentially giant hominid species that once inhabited Asia. It was first discovered and identified by von Koenigswald in 1935 when he described an isolated tooth that he found in a Hong Kong drugstore 11. The entire Gigantopithecus blacki fossil record, dated between the Early Pleistocene (~2.0 Mya) and the late Middle Pleistocene (~0.3 Mya 12), includes thousands of teeth and four partial mandibles from subtropical Southeast Asia 1,13,14. All the known Gigantopithecus blacki localities are situated in southern China, stretching from Longgupo Cave, just south of the Yangtze River, to the Xinchong Cave on Hainan Island, and, possibly, into northern Vietnam and Thailand 15,16. To address the evolutionary relationships between Gigantopithecus and extant hominoids, we performed protein extractions on dentine and enamel samples of a single molar (CF-B-16) found in Chuifeng Cave, China, that is morphologically assigned to Gigantopithecus blacki 7,8. The site is dated using multiple approaches to 1.9±0.2 Mya (Extended Data Figs. 1, 2). Enamel and dentine samples were processed using recently established digestion-free protocols optimized for extremely degraded ancient proteomes 17 (Methods). Enamel demineralization was replicated using two different acids, trifluoroacetic acid (TFA) and hydrochloric acid (HCl). Welker et ...
Over the past three decades, studies of ancient biomolecules-particularly ancient DNA, proteins, and lipids-have revolutionized our understanding of evolutionary history. Though initially fraught with many challenges, today the field stands on firm foundations. Researchers now successfully retrieve nucleotide and amino acid sequences, as well as lipid signatures, from progressively older samples, originating from geographic areas and depositional environments that, until recently, were regarded as hostile to long-term preservation of biomolecules. Sampling frequencies and the spatial and temporal scope of studies have also increased markedly, and with them the size and quality of the data sets generated. This progress has been made possible by continuous technical innovations in analytical methods, enhanced criteria for the selection of ancient samples, integrated experimental methods, and advanced computational approaches. Here, we discuss the history and current state of ancient biomolecule research, its applications to evolutionary inference, and future directions for this young and exciting field.
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Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative phosphoproteomics, we found 394 protein phosphorylation site changes in merozoites subjected to different ionic environments (high K+/low K+), 143 of which were Ca2+ dependent. These included a number of signaling proteins such as catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr) and calcium-dependent protein kinase 1 (PfCDPK1). Proteins of the 14-3-3 family interact with phosphorylated target proteins to assemble signaling complexes. Here, using coimmunoprecipitation and gel filtration chromatography, we demonstrate that Pf14-3-3I binds phosphorylated PfPKAr and PfCDPK1 to mediate the assembly of a multiprotein complex in P. falciparum merozoites. A phospho-peptide, P1, based on the Ca2+-dependent phosphosites of PKAr, binds Pf14-3-3I and disrupts assembly of the Pf14-3-3I-mediated multiprotein complex. Disruption of the multiprotein complex with P1 inhibits microneme secretion and RBC invasion. This study thus identifies a novel signaling complex that plays a key role in merozoite invasion of RBCs. Disruption of this signaling complex could serve as a novel approach to inhibit blood-stage growth of malaria parasites. IMPORTANCE Invasion of red blood cells (RBCs) by Plasmodium falciparum merozoites is a complex process that is regulated by intricate signaling pathways. Here, we used phosphoproteomic profiling to identify the key proteins involved in signaling events during invasion. We found changes in the phosphorylation of various merozoite proteins, including multiple kinases previously implicated in the process of invasion. We also found that a phosphorylation-dependent multiprotein complex including signaling kinases assembles during the process of invasion. Disruption of this multiprotein complex impairs merozoite invasion of RBCs, providing a novel approach for the development of inhibitors to block the growth of blood-stage malaria parasites.
Proteogenomics leverages information derived from proteomic data to improve genome annotations. Of particular interest are “novel” peptides that provide direct evidence of protein expression for genomic regions not previously annotated as protein-coding. We present a modular, automated data analysis pipeline aimed at detecting such “novel” peptides in proteomic data sets. This pipeline implements criteria developed by proteomics and genome annotation experts for high-stringency peptide identification and filtering. Our pipeline is based on the OpenMS computational framework; it incorporates multiple database search engines for peptide identification and applies a machine-learning approach (Percolator) to post-process search results. We describe several new and improved software tools that we developed to facilitate proteogenomic analyses that enhance the wealth of tools provided by OpenMS. We demonstrate the application of our pipeline to a human testis tissue data set previously acquired for the Chromosome-Centric Human Proteome Project, which led to the addition of five new gene annotations on the human reference genome.
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